Trans-system mechanisms against ischemic myocardial injury.

Trans-System Mechanisms Against Ischemic Myocardial Injury Shu Q. Liu,1* Xin-Liang Ma,2 Gangjian Qin,3 Qingping Liu,4 Yan-Chun Li,5 and Yu H. Wu1 ABSTRACT A mammalian organism possesses a hierarchy of naturally evolved protective mechanisms against ischemic myocardial injury at the molecular, cellular, and organ levels. These mechanisms comprise regional protective processes, including upregulation and secretion of paracrine cell-survival factors, inflammation, angiogenesis, fibrosis, and resident stem cell-based cardiomyocyte regeneration. There are also interactive protective processes between the injured heart, circulation, and selected remote organs, defined as trans-system protective mechanisms, including upregulation and secretion of endocrine cell-survival factors from the liver and adipose tissue as well as mobilization of bone marrow, splenic, and hepatic cells to the injury site to mediate myocardial protection and repair. The injured heart and activated remote organs exploit molecular and cellular processes, including signal transduction, gene expression, cell proliferation, differentiation, migration, mobilization, and/or extracellular matrix production, to establish protective mechanisms. Both regional and trans-system cardioprotective mechanisms are mediated by paracrine and endocrine messengers and act in coordination and synergy to maximize the protective effect, minimize myocardial infarction, and improve myocardial function, ensuring the survival and timely repair of the injured heart. The concept of the trans-system protective mechanisms may be generalized to other organ systems—injury in one organ may initiate regional as well as transsystem protective responses, thereby minimizing injury and ensuring the survival of the entire organism. Selected trans-system processes may serve as core protective mechanisms that can be exploited by selected organs in injury. These naturally evolved protective mechanisms are the foundation for developing protective strategies for myocardial infarction and injury-induced disorC 2015 American Physiological Society. Compr Physiol 5:167-192, ders in other organ systems. 2015.

Introduction The function of the heart is influenced largely by the rate of coronary blood flow (127, 175). While moderate-level insufficiency of coronary blood flow or myocardial ischemia causes an adaptive reversible reduction in myocardial contractility and metabolism without substantially influencing the myocardial survivability, severe myocardial ischemia, often a result of thrombosis and atherosclerosis, can cause deleterious consequences—myocardial injury, infarction, functional impairment, and failure. Through evolution, the heart has developed multiple protective mechanisms, including myocardial survival, reparative, and regenerative mechanisms. The survival mechanism is activated during the early phase of myocardial ischemia, when cell injury and death occur, and implemented through molecular signaling and/or gene expression processes that suppress cell injury and death, thereby enhancing myocardial tolerance to ischemia. These mechanisms are the foundation of therapeutic strategies, such as the well-recognized cardioprotective maneuvers ischemic preconditioning (short ischemia/reperfusion episodes induced in the heart or a remote organ to reduce the impact of a subsequent ischemic attack) (29,73,104,115,116,118,119,128,211, 226, 280, 288, 294, 314, 338, 339) and postconditioning (short

Volume 5, January 2015

ischemia/reperfusion episodes induced during early coronary reperfusion interventions following a heart attack to attenuate reperfusion injury) (118, 288, 292, 313-315, 344), as well as the natural protective process myocardial hibernation (adaptive reduction in myocardial contractility and metabolism in response to ischemia) (127, 249, 250, 259). The reparative mechanism is implemented through several injury-induced processes, including inflammation, angiogenesis, and fibrosis, enhancing perfusion of the ischemic myocardium, leukocyte infiltration, clearance of dead cell debris, and replacement of * Correspondence

to [email protected] Engineering Department, Northwestern University, Evanston, Illinois 2 Department of Emergency Medicine, Thomas Jefferson University Hospitals, Philadelphia, Pennsylvania 3 Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois 4 Carbohydrate and Lipid Metabolism Research Laboratory, College of Life Science and Technology, Dalian University, Dalian, China 5 Department of Medicine, Division of Biological Sciences, The University of Chicago, Chicago, Illinois Published online, January 2015 (comprehensivephysiology.com) DOI: 10.1002/cphy.c140026 C American Physiological Society. Copyright 1 Biomedical

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Trans-System Mechanisms Against Ischemic Myocardial Injury

damaged myocardium with fibrotic tissue. The regenerative mechanism involves activation of resident cardiac stem cells to generate functional cardiomyocytes, although the capacity of myocardial regeneration is limited (6, 176, 177, 188). Acting in coordination and synergy, these protective mechanisms ensure recovery of the heart from ischemic injury and reestablishment of a new homeostatic condition suitable for myocardial function in an ischemic environment. The cardioprotective mechanisms have evolved not only in the ischemic heart regionally (28, 114, 116, 128, 280, 328), but also in remote organs (169, 195-202, 232, 284, 298, 300). The regional protective mechanisms include upregulation and/or release of paracrine cell survival factors [e.g., adenosine (53, 213, 334), bradykinin (20, 102), opioids (21, 94), nitric oxide (149, 185, 328), IL-8 (170, 189), and VEGF (69, 154, 181, 192)], inflammation, and cardiomyocyte regeneration from resident stem cells (6,42,176,177,187,188), angiogenesis, and fibrosis. These mechanisms have been well documented (6,28,114,116,128,176,188,211,226,235,280,288) and will not be discussed in depth here. The remote protective mechanisms involve induction of messengers that trigger global inflammatory responses, upregulation and secretion of endocrine protective factors, and mobilization of selected cell types from selected remote organs. The endocrine factors and mobilized cells can access the ischemic myocardium through the circulatory system to enhance myocardial protection and repair. These interactive processes between the injured heart, circulation, and selected remote organs are defined as trans-system protective mechanisms. Such mechanisms are implemented through complex molecular signaling and cellular programs, and act in coordination and synergy with the regional mechanisms to maximize myocardial protection and repair. To date, the trans-system protective mechanisms have not been well recognized. Here, we address the induction, implementation, and significance of the transsystem protective mechanisms.

Induction of Trans-System Protective Mechanisms The trans-system protective mechanisms are likely induced and controlled by molecular messengers activated and released from the ischemic myocardium. The inflammationmediating factors cytokines from injured cells, including fibroblasts and endothelial cells, and activated leukocytes (153) may potentially serve as such messengers. Several cytokines, such as IL6, IL8, MCP1, TGFβ, and TNFα, are upregulated and released during the early period of myocardial ischemia (90-92, 199). These cytokines may participate in global inflammatory responses, stimulate upregulation and secretion of endocrine protective factors, and regulate cell mobilization from remote organs. Certain cytokines, such as IL-6, can activate circulating leukocytes, which in turn infiltrate remote organs to enhance inflammatory responses (199) and release additional cytokines to induce possibly endocrine

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protective factors. Indeed, many cytokines are capable of activating the transcription factors AP1, cJun, NFκB, and STATs (162), which potentially induce expression of several known endocrine cardioprotective factor genes, including α1acid glycoprotein type 2 (AGP2), fibroblast growth factor 21 (FGF21), and trefoil factor 3 (TFF3) (196, 202), as the promoter region of these genes contains consensus binding sites for the aforementioned transcription factors (see section Induction of Endocrine Protective Factors below). However, the exact cytokines responsible for activation of the transsystem protective mechanisms remain to be identified. Here, we briefly review the cytokine superfamily with a focus on the signaling mechanisms and the transcription factors involved. We also present evidence that supports cytokines as mediating factors for activating trans-system protective mechanisms. It is expected that, from the cytokine superfamily, messenger cytokines mediating the trans-system cardioprotective processes may be identified.

Cytokines as Potential Factors Activating Trans-System Protective Mechanisms Cytokines are soluble proteins secreted from various cell types, including monocytes, macrophages, B and T lymphocytes, mast cells, vascular endothelial cells, epithelial cells, fibroblasts, and stromal cells. These molecules participate in the regulation of inflammation, immunity, hematopoiesis, and cellular processes such as cell survival, proliferation, death, migration, and adhesion (13, 32). Selected cytokines, including IL6 (289, 321), cardiotrophin 1 (35, 262, 281), IL8 (170, 189), SDF1 (62), and TNF (146, 172, 229, 321), are involved in cell protective processes against injury. Cytokines are categorized into several families based on their sources, functions, receptors, and target cells, including the interleukin (IL), interferon (IFN), chemokine (chemotactic cytokines), tumor necrosis factor (TNF), and transforming growth factor β (TGFβ) families (32). Several hematopoietins such as erythropoietin, stem cell factor (c-kit ligand) (100), and colonystimulating factors (CSF) are also considered cytokines (23). Cytokines act on various receptors and signaling networks, participating in the regulation of selected cellular processes. There are several major types of cytokine receptors, including type I, type II, immunoglobulin superfamily, chemokine, TNF, and transforming growth factor β receptors (162, 233). Type I receptors are transmembrane proteins consisting of tandem repeats of Ig-like domains and sharing the signature motif WSXWS in the extracellular domain (97, 162, 233). These receptors form complexes with co-receptors, including gp130, common β chain, or common γ chain, and interact with selected interleukins and other protein ligands, including IL2β, IL3, IL4, IL5, IL6, IL7, IL9, IL11, IL12, IL13, IL15, IL21, IL23, IL27, granulocyte colony-stimulating factor (G-CSF), granulocytemacrophage colony-stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), and erythropoietin (Epo) (97). Type II receptors are similar to type I receptors in structure,



but lack the WSXWS motif (97). These receptors interact with interferons, including IFN α, IFN β, and IFN γ, and several other cytokines, including IL10 and IL22 (97,233). Immunoglobulin superfamily receptors share structural homology with immunoglobulins and interact with the IL1 family of cytokines, including IL1α, IL1β, and IL18 (31, 34, 171, 332). Chemokine receptors belong to the G protein-coupled receptor superfamily and are classified into four subfamilies based on the unique signature sequences of chemokines: CC receptors (CCRs) for chemokines with an N terminal CC motif, where C represents a cysteine residue, CXC receptors (CXCRs) for chemokines with an N-terminal CXC motif, where X represents a noncysteine residue, CX3C receptors (CX3CRs) for chemokines with an N-terminal CXXXC motif, and C receptors (CRs) for chemokines with an N-terminal C motif (3,11,224,253). TNF receptors are a family of trimeric transmembrane proteins interacting with TNFs and are characterized by the presence of a CXXCXXC motif (67,203,323). TGFβ receptors (TGFBRs) are single-pass serine/threonine kinase receptors with three members, TGFBR1, TGFBR2, and TGFBR3 (271). TGFBR1 and TGFBR2 interact with TGFβ1 in high affinity and with TGFβ2 in low affinity. TGFBR3 interacts with both TGFβ1 and TGFβ2. The signaling mechanisms of the cytokine receptors are discussed along with different cytokine families below.

Interleukins Interleukins are cytokines secreted from leukocytes, and to a lesser extent, from stromal cells, mast cells, epithelial cells, fibroblasts, and smooth muscle cells. To date, more than 40 interleukins have been identified (2, 39). Interleukins are categorized into several subfamilies based on their structures, target receptors, and functions, including the IL1, common γ chain, common β chain, IL6, IL10, IL12, and IL17 subfamilies. These cytokines are primarily involved in the regulation of inflammatory and immune responses. While the majority of interleukins initiate and promote inflammation and immunity, selected interleukins, such as IL1 receptor antagonist (IL1Ra), IL10, and IL35, suppress inflammatory and immune responses (2, 39). Interleukins play a critical role in mediating myocardial injury, protection, and repair. As interleukins activate AP1, NFκB, and STATs, transcription factors potentially binding to the gene promoter regions of several liverderived cardioprotective factors, including α1 acid glycoprotein type 2, fibroblast growth factor 21, and trefoil factor 3, these cytokines are considered candidates for identifying factors mediating trans-system cardioprotective processes. The IL1 subfamily consists of at least 11 members with varying structural homology, including IL1α, IL1β, IL1 receptor antagonist (IL1Ra), IL18, IL33, IL36Ra, IL36α, IL36β, IL36γ, IL37, and IL38 (2, 70, 71, 286, 326). These cytokines induce and regulate inflammatory and immune responses involving leukocytes and endothelial cells (70, 71). The signaling mechanisms of the IL1 subfamily founding molecules IL1α and IL1β have been well studied. Here,



we use these molecules to demonstrate the signaling mechanisms of the IL1 subfamily. Both IL1α and IL1β bind the ubiquitously expressed IL1 type I receptor (IL1R1). IL1Ra also binds this receptor, but does not cause signaling activities. It may competitively block IL1 binding to IL1R1 (70, 71, 326). Another receptor, known as IL1 type II receptor (IL1R2), also interacts with IL1α and IL1β, but does not activate intracellular signaling processes. Binding of IL1α or IL1β to IL1R1 induces the following sequential signaling events (326): (1) conformational changes in IL1R1; (2) recruitment of the IL1R1 cofactor IL1 receptor accessory protein (IL1RAcP) to IL1R1; (3) assembly and recruitment of two adaptor proteins known as myeloid differentiation primary response gene 88 (MYD88) and IL1 receptoractivated protein kinase 4 (IRAK4) to the IL1/IL1R1 complex (37, 193, 326); (4) autophosphorylation of IRAK4; (5) IRAK4-mediated phosphorylation and recruitment of IRAK1 and IRAK2 to the IL1/IL1R1 complex; (6) recruitment of TNF-associated factor 6 (TRAF6) to the IL1/IL1R1 complex; (7) dissociation of the IRAK1, IRAK2, and TRAF6 complex from IL1R1; (8) interaction of TRAF6 (serving as a ubiquitin E3 ligase) with the ubiquitin E2 ligase complex to cause attachment of the K63-linked polyubiquitin chain to several molecules, including IRAK1, TGFβ-activated protein kinase binding protein 2 (TAB2), TAB3, and TGFβactivated kinase 1 (TAK1, a member of the mitogen-activated protein kinase kinase kinase or MAPKKK family), inducing ubiquitination of these molecules; (9) association of ubiquitinated TAK1 with TRAF6 and mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase 3 (MEKK3), activating TAK1 and MEKK3; and (10) activation of the transcription factors NFκB and AP-1, causing expression of mitogenic and inflammatory genes. The common γ chain subfamily of cytokines is composed of IL2, IL4, IL7, IL9, IL13, and IL15 (2,210). These cytokines activate the common γ chain receptor, also known as CD132. This subfamily of cytokines is responsible primarily for regulating lymphocyte proliferation, differentiation, and activation (210). Here, IL2 is used to demonstrate the signaling mechanisms of this cytokine subfamily. IL2 interacts with its cognate receptor IL2 receptor α (IL2Rα), causing a cascade of intracellular signaling events (210): (1) forming a binary IL2Rα complex that stimulates recruitment of IL2Rβ and subsequently common γ chain to the IL2Rα complex; (2) phosphorylation of IL2Rβ by JAK1 and JAK3, protein tyrosine kinases constitutively associated with IL2Rβ and common γ chain, respectively; (3) recruitment of the transcription factor STAT5 to phosphotyrosine residues on IL2Rβ; (4) phosphorylation of the bound STAT5 molecules by JAKs and dimerization of STAT5; (5) translocation of STAT5 dimers to the nucleus and activation of target genes responsible for inflammatory and proliferative activities (98); and (6) internalization of the IL2/IL2R complex, degradation of IL2, IL2Rβ, and common γ chain, and recycling of IL2Rα to the cell surface (340). In addition, JAK-induced phosphorylation of IL2Rβ causes recruitment of the adaptor protein Shc to

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phosphotyrosine residues on the receptor and Shc in turn activates the mitogen-activated protein kinase and phosphatidylinositide 3-kinase pathways, resulting in cell survival and proliferation (210). The common β chain subfamily of cytokines consists of IL3, IL5, and GM-CSF, all of which are localized to chromosome 5 in the human and chromosome 11 in the mouse (43, 218). Each cytokine interacts with a receptor complex composed of a cytokine-specific type I receptor α chain and a common β chain (βc), participating in the regulation of myeloid cell development in a synergistic manner (279). IL3, IL5, and GM-CSF bind discrete receptors known as IL3 receptor α (IL3Rα), IL5Rα, and GM-CSFRα, respectively. These receptors are present in the monomeric form in unstimulated cells. Cytokine binding to a cognate receptor triggers the following intracellular signaling events (1, 65, 107, 279): (1) recruitment of common β chain to the cytokine/Rα complex, forming a heteromeric receptor complex; (2) autophosphorylation of the receptor-associated protein tyrosine kinases JAK1 and JAK2 (140); (3) phosphorylation of common β chain by JAKs, establishing phosphotyrosine docking sites for SH2 domain-containing molecules; (4) recruitment of STAT1 and STAT5 to the phosphotyrosine sites of common β chain; (5) phosphorylation of STAT1 and STAT5 by JAKs, resulting in STAT homo- or hetero-dimerization by reciprocal SH2 and phosphotyrosine interaction; and (6) translocation of STAT dimers to the nucleus and induction of gene expression. The IL6 subfamily of cytokines consists of IL6, IL11, leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 (CT1), cardiotrophin-like cytokine (CLC), and ciliary neurotrophic factor (CNTF) (299). Each cytokine interacts with a receptor complex composed of a specific α receptor and a common coreceptor known as glycoprotein 130 (gp130). These cytokines possess pleiotropic overlapping functions, responsible for initiating and regulating inflammatory and immune processes. Selected members of this family, including IL6 (289, 321), LIF (346), and CT1 (35, 262, 281), participate in protective responses against ischemic myocardial injury. In the event of cytokine upregulation, the following signaling processes take place (108, 123, 124, 225, 299): (1) binding of a cytokine ligand to a specific α receptor – IL6 receptor α (IL6Rα) for IL6, IL11Rα for IL11, LIFRα for at least four ligands including LIF, CNTF, CT1, and CLC, and OSMRα or LIFRα for OSM; (2) recruitment of gp130 to the cytokine/receptor complex, with two gp130 molecules to each IL6Rα or IL11Rα and a single gp130 molecule to LIFRα or OSMRα; (3) autophosphorylation of JAK1 and JAK3, which are constitutively associated with the receptors; (4) receptor phosphorylation on tyrosine residues by JAKs, creating docking sites for SH2 domain-containing molecules; (5) recruitment of STAT3 molecules to the phosphotyrosine sites, resulting in STAT3 dimerization; (6) translocation of STAT3 dimers to the nucleus, inducing expression of inflammatory, protective, and/or proliferative genes. The IL10 subfamily of cytokines encompasses IL10, IL19, IL20, IL22, IL24, IL26, IL28A, IL28B, and IL29

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(82, 233, 266). These cytokines regulate inflammatory processes with diverse actions and play critical roles in maintaining epithelial homeostasis and controlling wound healing. These cytokines are categorized into three groups based on function—the IL10, IL20, and type III interferon (IFN) groups (233). IL10, the founding IL10 family cytokine (82), is the only member for the IL10 group. This cytokine acts on leukocytes and exerts an anti-inflammatory action, preventing excessive inflammation-induced adverse effects. The IL20 group includes IL19, IL20, IL22, IL24, and IL26 (265). These cytokines target and protect epithelial cells from microbial infection and promote wound healing. The type III IFN group is composed of IL28A, IL28B, and IL29 (233). These cytokines participate in protective responses against viral infection. Overall, the core function of the IL10 subfamily is to protect cells, tissues, and organs from injury and infection. This family of cytokines interacts with type II cytokine receptors and causes the following signaling events (82, 83, 233, 266): (1) binding of a cytokine with a cognate receptor complex composed of discrete α and/or β chains— IL10R1 and IL10R2 for IL10, IL20R1 and IL20R2 for IL19, IL20R1 or IL22R for IL20, IL22R and IL10R2 for IL22, IL20R1 for IL26, and IL28R for IL28A; (2) autophosphorylation of various JAKs associated with the receptor complex, for instance, JAK1 and TYK2 for IL10R1 and IL10R2, respectively (83, 129); (3) tyrosine phosphorylation of cytokine receptors by JAKs; (4) recruitment of STATs such as STAT1, STAT3, and/or STAT5 to the phosphotyrosine sites; (5) homoor hetero-dimerization of STATs; and (6) translocation of STAT dimers to the nucleus and induction of gene expression. The IL12 subfamily of cytokines consists of IL12, IL23, IL27, and IL35. Each cytokine is composed of an α and β chain. These chains can form distinct cytokines by selective combinations and share homology with the IL6 family cytokines (2, 311). For instance, a p35α chain can couple with a p40β chain to form IL12, whereas a p19α chain and a p40β chain form IL23 (231). The IL12 subfamily cytokines exhibit diverse functions in immune and inflammatory responses to microbial infection. For instance, IL12 and IL23 promote inflammatory responses, whereas IL27 and IL35 inhibit these responses. The following processes are induced in the presence of the IL12 subfamily cytokines (311): (1) binding of cytokines to cognate receptor complexes— IL12 to the IL12Rβ1/IL12Rβ2 complex (246), IL23 to the IL23R/IL12Rβ1 complex (236), IL27 to the IL27R/gp130 complex (241), and IL35 to the IL12Rβ2/gp130 complex (55); (2) autophosphorylation of JAKs—JAK2 and TYK2 for IL12 and IL23 receptors, respectively, and JAK1 and JAK2 for IL27 and IL35 receptors, respectively (231); (3) recruitment and phosphorylation of STATs—STAT4 for IL12 receptors, STAT3 and STAT4 for IL23 receptors, STAT1 and STAT3 for IL27 receptors, and STAT1 and STAT4 for IL35 receptors (231); (4) dimerization of STATs; and (5) translocation of STAT dimers to the nucleus and induction of target gene transcription. The discrete signaling players control the diverse functions of this cytokine subfamily (311).



The IL17 subfamily of cytokines consists of IL17A, IL17B, IL17C, IL17D, IL17E (also known as IL25), and IL17F (148, 325). These cytokines share varying degrees of homology in structure and regulate inflammatory and immune responses. IL17A and IL17F initiate and promote inflammatory responses (143,319), IL17B, IL17C, and IL17D induce expression of proinflammatory genes (190, 293, 333, 335), whereas IL17E regulates allergic responses (86, 234). These cytokines function through interactions with several heterodimeric receptor complexes—IL17A and IL17F act on the IL17 receptor A (IL17RA)/IL17RC complex (44, 45, 145), IL17E recognizes the IL17RA/IL17RB complex (44, 45, 145), and IL17C targets the IL17RA/IL17RE complex (45, 252, 291). The signaling mechanisms of the IL17 subfamily cytokines have not been well studied. Limited research has demonstrated that binding of IL17A or IL17F to cognate receptor activates several intracellular signaling molecules, including tumor-necrosis factor receptorassociated factor 6 (TRAF6) (276) and NFkB activator 1 (ACT1) (151). These molecules are involved in regulating inflammatory and immune responses. However, the exact mechanisms remain poorly understood.


and activation of receptor-associated JAKs—TYK2 and JAK1 for IFNαR1 and IFNαR2, respectively, JAK1 and JAK2 for IFNγR1 and IFNγR2, respectively, and JAK1 and TYK2 for IL28R1 and IL10R2, respectively; (2) phosphorylation of IFN receptors by JAKs, establishing phosphotyrosine docking sites; (3) recruitment of STATs to the phosphotyrosine sites—STAT1, STAT2, STAT3, STAT4, and/or STAT5 for type I IFNs, STAT1, STAT3, and/or STAT5 for type II IFN, and STAT1, STAT2, and/or STAT3 for type III IFNs; (4) phosphorylation of STATs by JAKs; (5) homo- or heterodimerization of STATs and translocation of STAT dimers to the nucleus; and (6) induction of target gene expression. The JAK-STAT signaling cascades may network with other signaling cascades, including the MAPK, PI3K-Akt, and NFκB cascades. Through these diverse, yet collaborative and synergistic, signaling processes, IFNs regulate effectively immune and inflammatory responses to microbial infection and injury (239, 244). As interferons can activate STATs, AP1, and NFκB, transcription factors capable of binding to the genes of several liver-derived cardioprotective factors, including AGP2, FGF21, and TFF3, these cytokines are potential candidates for identifying factors mediating the trans-system cardioprotective processes.

Interferons Interferons (IFNs) are a cytokine family categorized into three subfamilies: type I, type II, and IFN-like or type III IFNs (80, 239, 244). The type I subfamily comprises a number of IFNα proteins (IFNα1, α2, α4, α5, α6, α7, α8, α10, α13, α14, α16, α17 and α21), IFNβ, IFNδ, IFNε, IFNκ, IFNτ, and IFNω. The type II subfamily includes IFNγ only. The type III subfamily includes IL28A, IL28B, and IL29, also known as IFNλ2, IFNλ3, and IFNλ1, respectively (89, 306). All IFNs, except for IFNδ and IFNτ, have been found in the human (186, 257). Type I IFNs are primarily expressed in B- and T-lymphocytes and macrophages and, to a lesser extent, in fibroblasts and endothelial cells. These cytokines are induced in response to viral infection for cell protection (52,80). Several cytokines, including IL1, IL2, IL12, and TNF (109), can activate selected leukocytes, including natural killer cells and macrophages, to enhance antigen presentation to T cells, thereby promoting expression of interferons and resistance to viral infection. The function of type III IFNs is similar to that of type I (167, 282, 312). IFNγ is produced by T lymphocytes and is a key player in innate and adaptive immunity against viral and bacterial infection (10). IFNγ regulates nitric oxide production (147) and contributes to tumor surveillance and suppression (22, 273). An IFN interacts with a cognate receptor complex composed of two subunits—IFNα receptor 1 (IFNαR1 or IFNAR1) and IFNαR2 (IFNAR2) for type I IFNs, IFNγR1 (IFNGR1) and IFNγR2 (IFNGR2) for type II IFN, and IL28R1 and IL10R2 for type III IFNs (239, 244). Binding of an IFN to its receptor complex causes dimerization of the receptor subunits, resulting in sequential intracellular signaling events, including (84, 239, 244): (1) autophosphorylation


Chemokines Chemokines are a large family of chemotactic cytokines composed of about 50 members and are categorized into four subfamilies based on the arrangement of cysteine (C) residues— CC ligands (CCLs) for chemokines with a CC motif, CXC ligands (CXCLs) for chemokines with a CXC motif, where X represents a noncysteine amino acid residue, CX3C ligands (CX3CLs) for chemokines with a CXXXC motif, and XC ligands (XCLs) for chemokines with a XC motif (3, 11, 206, 224, 253, 261). The name of each cytokine is followed by a number, indicating the chronological order of chemokine discovery. Chemokines interact with specific G protein-coupled receptors that are grouped based on the chemokine subfamily names—CC receptors (CCRs) for CCLs, CXCRs for CXCLs, CX3CRs for CX3CLs, and XCRs for XCLs. The name of each receptor is followed by a number, indicating the chronological order of receptor discovery. The primary function of chemokines is to induce and control cell chemotaxis, regulate cell migration during development and physiological processes, and promote leukocyte extravasation and infiltration during inflammatory and immune responses (3, 81). The CCL subfamily consists of 28 chemokines identified as CCL1-CCL28 (note that the well-studied chemokines monocyte chemotactic protein 1 (MCP1), MCP2, MCP3, and MCP4 are named as CCL2, CCL8, CCL7, and CCL13, respectively) (11). These chemokines interact with 10 CC receptors defined as CCR1-CCR10. Each receptor may interact with one or more CCLs. For instance, CCR1 interact with CCL3, CCL5, CCL7, CCL13-16, and CCL23, whereas CCR8 accepts only CCL1 (3, 11, 56). The CXCL subfamily is composed of 16 chemokines including CXCL1-CXCL16

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(note that the well-studied chemokine stromal cell derived factor 1 (SDF1) is named as CXCL12). These chemokines act on eight CXCRs, including CXCR1, CXCR2, CXCR3A, CXCR3B, and CXCR4-7. CXCR4, CXCR5, CXCR6, and CXCR7 each interacts with one CCL (CXCL12, CXCL13, CXCL16, and CXCL12, respectively), whereas other CXCRs are promiscuous. For instance, CXCR1 recognizes CXCL6, CXCL7, and CXCL8 (3, 11). CXCL12 or SDF1 has been shown to participate in cardioprotective responses to ischemic myocardial injury, mitigating myocardial infarction via interaction with CXCR4 (135, 136, 270). CXCL12 has also been shown to be upregulated in response to limb ligation-based remote ischemic preconditioning in an animal model, contributing to myocardial protection against ischemic injury (62). The XCL subfamily consists of two members, XCL1 and XCL2. Both chemokines interact with XCR1, the only receptor known for this subfamily. The CX3CL subfamily includes only one member, CX3CL1. This chemokine acts on CX3CR1 (3, 11). Chemokines regulate biological processes by activating the pertussis toxin-sensitive G protein-coupled receptor signaling pathways (56, 81, 206). G-proteins are associated with GDP in unstimulated cells. Upon ligand binding, receptor conformational changes induce exchange of GDP for GTP. Gproteins dissociate into Gα and Gβ subunits. The Gβ subunit can activate the membrane-associated enzyme phospholipase Cβ2. Activated phospholipase Cβ2 hydrolyzes membrane phosphatidylinositol 4,5-biphosphate (PIP2 ) to inositol 1,4,5triphosphate (IP3 ) and diacylglycerol. These lipid molecules exert distinct functions. IP3 can diffuse through the cytoplasm and acts on Ca++ channels in the endoplasmic reticulum (ER), resulting in Ca++ release (56, 81, 206). The other lipid molecule, diacylglycerol, together with Ca++ , can activate the Ca++ -dependent serine/threonine kinase protein kinase C (PKC). Activated PKC can phosphorylate two substrate proteins: mitogen-activated protein kinase (MAPK) and Iκ-B. Phosphorylated MAPK activates transcription factors including cFos and cJun (molecules that can form a homodimeric or heterodimeric transcription factor known as activating protein 1 or AP1), causing mitogenic gene expression (56, 81, 206). IκB forms a complex with NFκB, a transcription factor that regulates expression of inflammatory and mitogenic genes. Phosphorylation of IκB induces release of NFκB, which is translocated to the cell nucleus to induce gene expression (223). Given that chemokines are capable of activating AP1 and NFκB, transcription factors potentially binding to the gene promoters of several liver-derived cardioprotective factors, including AGP2, FGF21, and TFF3, chemokines are considered candidates for identifying factors mediating transsystem cardioprotective processes.

Tumor necrosis factor family proteins The TNF family consists of at least 18 members, including tumor necrosis factor ligand superfamily member (TNFSF) 1A, TNFSF1B, TNFSF3-TNFSF13, TNFSF13B, TNFSF14,

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TNFSF15, TNFSF18, ectodysplasin 1 (EDA1), and EDA2 (18, 161, 323). Note that these are standardized terms, and the well-studied TNF family proteins TNF (also known as TNFA or TNFα), lymphotoxin α (LTα), and LTβ are renamed as TNFSF1A, TNFSF1B, and TNFSF3, respectively (323). These cytokines interact with cognate receptors to activate discrete intracellular signaling networks and regulate inflammatory responses (101) and cell processes, including cell apoptosis, survival, and proliferation (18, 161, 323). Selected TNF family cytokines, such as TNFSF1A or TNF, are involved in the regulation of protective responses to ischemic myocardial injury (164). The function of the TNF family proteins is receptor dependent. To date, about 29 TNF receptors have been identified (67, 203). In taxonomy, each receptor comes with a number that usually matches the number of the TNF ligand that binds the receptor. For instance, the TNF receptor superfamily member 1A or TNFRSF1A (also known as TNFR1) interacts with the ligand TNFSF1A. The TNF family receptors are categorized into three groups based on their structures and functions. Group I receptors, characterized by the presence of a death domain in the cytoplasmic region, include TNFRSF1A (TNFR1), TNFRSF6 (Fas), TNFRSF25 (death receptor 3 or DR3), TNFRSF10A (TRAIL-R1), TNFRSF10B (TRAIL-R2), and TNFRSF21 (DR6) (67). These receptors activate apoptosis regulatory networks, resulting in cell death. Group II receptors, characterized by the presence of TNF receptor-associated factor-interacting motifs (TIMs) in their cytoplasmic region, include TNFRSF1B (TNFR2), TNFRSF3 (LTβR), TNFRSF4 (Ox40), TNFRSF5 (CD40), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (4-1BB), TNFRSF11A (RANK), TNFRSF12A (Fn14), TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFRSF14 (HVEM), TNFRSF16 (p75NGFR), TNFRSF17 (BCMA), TNFRSF18 (CD357), TNFRSF19 (TROY), TNFRSF19L (RELT), EDA1R, and EDA2R (67, 316, 317, 322). These receptors activate several signaling networks, including the NFκB, ERK1/2, JNK, and PI3K-Akt networks, promoting cell survival and proliferation (67, 316, 317). Group III receptors include TNFRSF10C (TRAIL-R3), TNFRSF10D (TRAIL-R4), decoy-R3, and osteoprotegerin. These receptors do not contain cytoplasmic motifs for signal transduction, but serve as decoy receptors, competing for ligands and thereby dampening the activity of other TNF family receptors (67). Group I TNF-induced cell death is regulated by apoptosis signaling networks. A key feature of these signaling networks is the presence and participation of an adaptor death protein in signal transduction. TNFRSF6 (Fas), TNFRSF10A (TRAIL-R1), and TNFRSF10B (TRAIL-R2) interact with the adaptor protein Fas-associating death domain-containing protein (FADD), whereas TNFRSF1A (TNFR1) and TNFRSF25 (DR3) recognize TNFR1-associated death domain protein (TRADD) (50, 160). These two types of death receptor/ domain protein combination cause distinct signaling events, but the outcome is the same—cell death. Here, the Fas system is used to demonstrate the signaling mechanisms of



apoptosis. Binding of Fas-L to Fas causes two types of cell death signaling events, defined as type I and type II signaling. Type I signaling involves the following processes (17, 67, 316, 317): (1) interaction of Fas death domain with Fas-associating death domain-containing protein in response to Fas-L binding, forming the death-inducing signaling complex (DISC); (2) recruitment of caspase 8 to the receptor complex and interaction of the death effector domains (DEDs) of caspase 8 with the death effector domains of Fas-associating death domain-containing protein, resulting in caspase 8 activation; (3) processing of downstream procaspases by activated caspase 8, resulting in activation of effector caspases, including caspase 3; and (4) degradation of target proteins by activated caspase 3, resulting in cell death. Type II apoptosis signaling involves mediating factors different from those for type I signaling, but the end-result is the same—caspase 3-induced protein degradation and cell death. This type of cell death is induced by the following signaling events (67, 316, 317): (1) binding of Fas-L to Fas, resulting in interaction of Fas-associating death domain-containing protein with Fas; (2) recruitment and activation of caspase 8; (3) cleavage of the protein Bid by caspase 8, releasing a truncated proapoptotic protein known as tBid (191); (4) association of tBid with the external mitochondrial membrane (191); (5) BAK oligomerization by tBid, inducing pore formation in the mitochondrial membrane (327); (6) release of cytochrome C from the mitochondria to the cytoplasm (327); (7) interaction of cytochrome C with apoptotic protease activating factor 1 (Apaf-1) and recruitment of caspase 9 to the cytochrome C/Apaf-1 complex, forming apoptosomes (285, 345); (8) cleavage of procaspase 3 into active caspase 3 by apoptosomes; and (9) protein degradation by caspase 3, resulting in cell death. Both type I and type II apoptosis may occur in myocardial ischemia and reperfusion injury, contributing to myocardial infarction and heart failure. The TNFR1 system exhibits two distinct behaviors— inducing cell death or survival, depending on the genetic makeup, state, and environment of the target cell (164, 275). The cell death signaling mechanisms are similar to those for the Fas system described above, except that TNFR1associated death domain protein is utilized instead of Fasassociating death domain-containing protein. The end result is the same—caspase 3-mediated cell death. In selected cell types at a given state, for example, inflammation in injury, TNF-activated TNFR1-associated death domain protein may recruit and activate TNF receptor-associated factor 1 (TRAF1), TRAF2, and receptor-interacting protein (RIP), leading to activation of the NFκB and JNK signaling networks (67, 134, 164). These signaling events promote inflammatory responses and cell survival, proliferation, and migration (67, 134, 164). In ischemic myocardial injury, TNF is upregulated in injured and inflamed cells (91, 92, 164), potentially exerting two distinct effects – exacerbating or mitigating myocardial injury (164, 275). These distinct effects depend on the TNF receptor types. TNF-induced activation of TNFR1 intensifies



ischemic myocardial injury, whereas TNFR2 activation causes an opposite effect (164). Thus, the relative level and distribution of the TNF receptor types ought to be taken into account in TNF research. Furthermore, TNF mediates the process of ischemic preconditioning-induced myocardial protection against myocardial injury in a subsequent heart attack (164). In TNF-deficient mice, the protection effect of ischemic preconditioning is attenuated (139). This process is dependent on the dose of TNF—a low dose of TNF promotes the cardioprotective effect of ischemic preconditioning, whereas a high dose intensifies myocardial injury (164). The cardioprotective effect of TNF is mediated by several signaling networks, including the protein kinase C (178), JAKs/STATs (85,179,297), and PI3K/Akt networks (164,173). As the TNF family cytokines can activate the transcription factors AP-1, NFκB, and STATs, which potentially bind to the genes of the liver-derived cardioprotective factors, including α1-acid glycoprotein type 2 (AGP2), fibroblast growth factor 21 (FGF21), and trefoil factor 3 (TFF3), these cytokines may be considered candidates for identifying factors mediating the trans-system cardioprotective processes.

Transforming growth factor β family proteins The transforming growth factor β (TGFβ or TGFB) family is composed of at least 29 members, including 3 TGFβs (TGFβ 1-3), 4 activin βs (activin βA-D), the protein nodal, 10 bone morphogenetic proteins (BMPs), and 11 growth and differentiation factors (GDFs) (271). These factors participate in the regulation of cell proliferation, differentiation, apoptosis, and/or migration. In particular, selected proteins from this family regulate embryogenic processes such as cell fate determination, gastrulation, and morphogenesis (271). Almost all TGFβ family proteins are produced as dimeric precursors. The proteases subtilisin-like proprotein convertases (SPCs) can cleave TGFβ precursors, generating mature TGFβ homodimers or heterodimers. These dimeric forms are required for appropriate TGFβ actions (271). The function of the TGFβ family proteins is receptordependent. There are two types of TGFβ receptor: type I and type II. Type I receptors include activin β receptor 1 (ACVR1), ACVR1B, ACVR1C, activin A receptor type IIlike 1 (ACVRL1), BMP receptor 1A (BMPR1A), BMPR1B, and TGFβ receptor 1 (TGFBR1) (271). Type II receptors include ACVR2, ACVR2B, anti-Mullerian hormone receptor type II (AMHR2), BMPR2, and TGFBR2 (271). Each receptor comprises an extracellular, a transmembrane, and a serine/threonine kinase-containing intracellular domain and can interact with multiple TGFβ ligands. Both type I and type II receptors are present as dimers in unstimulated cells. Binding of a TGFβ ligand to its receptor brings a type I dimer to a type II dimer in close proximity, forming a heterotetrameric complex. A type II receptor, possessing a constitutively active serine/threonine kinase, can phosphorylate a type I receptor on selected serine and threonine residues within the intracellular domain. The phosphorylated receptor

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enables recruitment of the intracellular proteins SMADs [homologs of both the Caenorhabditis elegans protein SMA and the Drosophila protein mothers against decapentaplegic or MAD (269, 277)], including SMAD1, SMAD2, SMAD3, SMAD5, and/or SMAD8, to the receptor complex. The type I receptor serine/threonine kinase induces phosphorylation on 2 serine residues of each SMAD at the C-terminus. The phosphorylated SMADs dissociate from the receptor complex and combine with SMAD4, forming SMAD complexes. These complexes, serving as transcription factors, are translocated to the cell nucleus and cause chromatin histone modifications, promoting SMAD binding to target genes and inducing gene expression (79, 260, 271). Given the role of the TGFβ signaling networks in the regulation of cell proliferation, differentiation, apoptosis, and migration, the TGFβ family proteins may be involved in protective responses to myocardial injury.

Hematopoietins There are several cytokines that regulate hematopoiesis and are referred to as hematopoietins. These include erythropoietin (Epo), stem cell factor (SCF), and three colony stimulating factors—granulocyte colony-stimulating factor (G-CSF, also known as colony-stimulating factor 3), granulocyte-macrophage colony-stimulating factor (GM-CSF, also known as colony stimulating factor 2), and macrophage colony-stimulating factor (M-CSF, also known as colony stimulating factor 1) (110). Other cytokines, including IL1, IL3, IL4, IL5, IL6, IL11, IL12, LIF, and TGFβ, are also involved in hematopoiesis and are considered hematopoietins. These cytokines are discussed in the sections above. Here, Epo, SCF, and colony stimulating factors are addressed. Erythropoietin (Epo) is a glycosylated cytokine expressed and released from the kidney during the adult stage and the liver during the embryonic stage (324). The primary function of Epo is to regulate erythrocyte formation by acting on erythroid progenitor cells in the bone marrow in the adult and the liver in the fetus (88). The circulating level of Epo is relatively low under physiological conditions, but can be rapidly upregulated in response to environmental and pathological changes that demand erythropoiesis, such as hypoxia and anemia (324). Epo is also involved in the regulation of wound healing (112) and protection against ischemic cerebral (38, 287) and myocardial injury (27, 220, 238). However, clinical trials have failed to demonstrate the neuro- and cardio-protective effect of Epo in ischemic injury (99, 296). Epo exerts its effects by interacting with Epo receptor (EpoR) expressed primarily in erythroid progenitor cells (324). EpoR is a type I cytokine receptor characterized by the presence of immunoglobulin-like domains and the signature motif of WSXWS in the extracellular region. Binding of Epo to EpoR causes a cascade of signaling events, including (324): (1) dimerization of EpoRs; (2) activation of JAK2, which is constitutively associated with EpoR; (3) tyrosine phosphorylation of EpoR on the intracellular domains by JAK2, establishing docking sites for SH2 domain-containing

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molecules; (4) recruitment of the transcription factor STAT5 to the phosphotyrosine sites, resulting in activation and dimerization of STAT5s; and (5) translocation of STAT5 dimers to the nucleus and induction of gene expression. Stem cell factor (SCF) is a cytokine expressed primarily in embryonic organs and is responsible for regulating cell survival, proliferation, differentiation, and migration. In the bone marrow, SCF is expressed in stromal cells and plays a critical role in regulating hematopoiesis (258). SCF is present in soluble and cell membrane-anchored forms, determined by distinct RNA splicing and proteinase-based cleaving processes (258). The precursor of the soluble form is deployed to the cell membrane when produced, containing extracellular, transmembrane, and intracellular domains. The extracellular domain of the SCF precursor is cleaved by MMP9, resulting in soluble SCF formation. Soluble SCFs become active by dimerization in the extracellular space. A SCF dimer can interact with the protein tyrosine kinase-coupled receptor c-Kit in hematopoietic stem cells (100, 258, 341). Binding of SCF to c-Kit causes activation of the following cascade (258): (1) dimerization of c-Kit receptors; (2) autophosphorylation of the c-Kit intracellular domains on tyrosine residues, establishing phosphotyrosine docking sites for SH2 domain-containing molecules; (3) recruitment of multiple intracellular signaling molecules, including growth factor receptor-bound protein 2 (Grb2), Src family kinases, and phosphatidylinositide 3kinase (PI3K), to the phosphotyrosine sites; (4) activation of various survival and mitogenic signaling pathways, including the mitogen-activated protein kinase (MAPK) and Akt pathways; and (5) activation of various transcription factors including cFos, cJun, and/or AP-1, resulting in expression of survival and mitogenic genes. Colony-stimulating factors are soluble glycoproteins responsible primarily for regulating leukocyte proliferation, differentiation, and mobilization. These factors are induced in response to various stimulating factors, including 12-o-tetradecanoylphorbol-13-acetate (TPA), bacterial LPS, IL1, IL3, IL4, interferon γ, and TNF (66, 110, 272). Among the three known colony-stimulating factors, granulocyte colony-stimulating factor (G-CSF) is expressed in monocytes, macrophages, endothelial cells, and fibroblasts, and was originally identified as a factor regulating the proliferation and differentiation of primarily neutrophils (16, 66, 110). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in endothelial cells, fibroblasts, smooth muscle cells, macrophages, and stromal cells (110), and is responsible for regulating the formation of granulocytes and macrophages from bone marrow hematopoietic progenitor cells (110). Macrophage colony-stimulating factor (M-CSF) is found in similar cell types and responsible for the development of macrophages (110). These colonystimulating factors are also involved in inflammatory and immune responses (110, 256). Upregulation or administration of either colony-stimulating factor induces mobilization of hematopoietic stem and progenitor cells from the bone marrow (110, 305). In particular, G-CSF is upregulated in




response to myocardial ischemia to mobilize bone marrow cells to the circulation, contributing to myocardial protection (75, 204, 240, 283, 300, 307). The three colony-stimulating factors act on distinct signaling networks. G-CSF and GM-CSF interact with G-CSF receptor (G-CSFR) and GM-CSFR, respectively, members of the type I cytokine receptor family (110, 272). Binding of GCSF and GM-CSF to their receptors causes activation of the receptor-associated protein tyrosine kinases JAKs, including JAK1, JAK2, and TYK2, and the transcription factors STATs, including STAT1, STAT3, and STAT5, which induce expression of proliferative and inflammatory genes. These concepts and processes are discussed in the sections above. In contrast, M-CSF interacts with protein tyrosine kinase-coupled M-CSF receptor (M-CSFR) (243), resulting in receptor dimerization and autophosphorylation of the receptor intracellular domains, establishing phosphotyrosine docking sites for SH2 domain-containing molecules. Several SH2 domaincontaining molecules, including Grb2, Src family kinases, and PI3K, are capable of binding to the phosphotyrosine sites of M-CSFR, leading to activation of the MAPK and Akt kinase signaling cascades, which in turn induce expression of cell survival and proliferative genes (137, 243).

identified from the liver of the mouse with ischemic myocardial injury, including α1-acid glycoprotein type 2 (AGP2), bone morphogenetic protein binding endothelial regulator (BMPER), fibroblast growth factor 21 (FGF21), neuregulin 4 (NRG4), and trefoil factor 3 (TFF3) (196). FGF21 has also been found in the adipose tissue in myocardial ischemia/reperfusion injury (197). These proteins were discovered based on the observations that transplantation of hepatic cells or administration of liver extract from donor mice with acute myocardial ischemia, but not sham operation, into the circulation of recipient mice mitigated myocardial infarction, suggesting the presence of cardioprotective factors in myocardial ischemia-conditioned liver (202). A genome-wide profiling analysis has demonstrated upregulation of 7 soluble protein genes, including five genes encoding the proteins named above and the chemokine CXC ligand 13 (CXCL13) and proteoglycan 4 (PRG4) genes, in hepatocytes isolated from mice with myocardial ischemia/reperfusion injury (Fig. 1) (202). Functional screening tests—administrating each of the seven upregulated proteins immediately following ischemic myocardial injury and analyzing subsequent changes in the degree of acute myocardial infarction—have suggested AGP2, BMPER, FGF21, NRG4, and TFF3 as cardioprotective factors (Fig. 2) (196). The expression of these proteins in hepatocytes has been confirmed by immunoblot analysis (196). Once upregulated, the proteins can be released into the circulatory system as demonstrated by ELISA (196), and are capable of accessing the ischemic myocardium, eliciting cardioprotective actions. In the following section, the

Induction of endocrine protective factors Experimental myocardial ischemia induces upregulation and secretion of endocrine protective proteins from the liver and adipose tissue. To date, at least five such proteins have been AGP2

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Figure 1 Genome-wide profiling of mRNA transcription demonstrating upregulation of AGP2, BMPER, CXCL13, FGF21, NRG4, PRG4, and TFF3 mRNAs in hepatocytes from mice with sham operation (time 0) or myocardial ischemia. The “Relative level” is defined as a fold-change in reference to the sham control level. SAA1 and SAA2, acute phase protein genes, were used as positive controls for the presence of liver inflammation. The dashed lines represent transcription of the β actin gene (202).


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Identification of liver-derived cardioprotective proteins. (A) TTC-stained left ventricular specimens from mice with 24-hr myocardial ischemia administered with PBS or recombinant AGP2, BMPER, CXCL13, FGF21, NRG4, PRG4, or TFF3 immediately post myocardial ischemia (50 ng/gm each, single dose, IV). A combination of AGP2, BMPER, FGF21, NRG4, and TFF3, identified as cardioprotective proteins, was administered with a similar strategy (50 ng/gm each). The intact myocardium was stained red and the infarct remains unstained. Scale bar: 1 mm. (B) Graphic representation of the influence of PBS, AGP2, BMPER, CXCL13, FGF21, NRG4, PRG4, or TFF3 administration on the degree of myocardial infarcts at 24 hrs. The influence of AGP2, BMPER, FGF21, NRG4, and TFF3 in combination is also presented (5 SPs or secreted proteins). Means and SDs are presented (n = 8 each group). ∗ P < 0.05, ∗∗ P < 0.01, and ∗∗∗ P < 0.001 for comparisons between hepatic protein(s) and PBS. # P < 0.05 and ### P < 0.001 for comparisons between a single hepatic protein and the combination of AGP2, BMPER, FGF21, NRG4, and TFF3 (196).

structure and function of the five liver-derived cardioprotective factors are briefly described.

Characteristics of endocrine protective factors Among the five liver-derived cardioprotective factors, α1Acid glycoprotein type 2 (AGP2), also known as orosomucoid 2 (ORM2), is heavily glycosylated (about 45%) and negatively charged due to the presence of sialic acids (68,87,222). AGP2 is a plasma protein synthesized primarily in hepatocytes (87, 216, 222). The expression of AGP2 is regulated by a number of inflammatory mediators including IL1β, IL6, TNF, and glucocorticoids (87). AGP2 is an acute-phase protein that can be upregulated up to twofold to fivefold in response to injury (68, 130, 131, 217). This protein has been known to regulate inflammatory and immune responses with the following specific functions: (1) inhibiting T-cell development and proliferation (51); (2) inhibiting neutrophil chemotaxis and proliferation (58, 174); (3) inhibiting platelet aggregation (5, 57); (4) stimulating expression and secretion of IL1, IL6, IL12, and TNF from monocytes and macrophages (33, 295); (5) promoting fibroblast proliferation and wound healing (194, 208); (6) protecting tissues and organs from

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bacterial infection and inflammatory shock (93, 131); (7) antagonizing the effect of histamine on endothelial permeability and preventing endothelial leakage (242); (8) inhibiting TNF-mediated apoptosis (309, 310); and (9) protecting the kidney (60) and intestine (329) from ischemia/reperfusion injury. Thus, AGP2 is considered a protective factor. Bone morphogenetic protein-binding endothelial regulator (BMPER), also known as crossveinless 2 (CV2), was originally found in developing Flk1-positive endothelial cells (221). This protein can be secreted into the extracellular space to mediate cell activities by interacting with bone morphogenetic protein (BMP) 4, a TGFβ family protein involved in regulating embryonic mesoderm specification, endothelial cell differentiation, angiogenesis, nephron generation, and development of osteoblasts and chondrocytes (122,141,221). However, the effect of BMPER on BMP4 is controversial. While several investigations demonstrated an inhibitory effect of BMPER on the activity of BMP4 (25, 54, 221), others supported an opposite effect (122,141,150,251,254). More recent investigations have provided insights into the mechanisms of BMPER-mediated opposing effects. BMPER may serve as a pro- or anti-BMP4 factor depending on the relative level of BMPER (155, 278). At a low level, BMPER may activate



BMP4 by promoting BMP4 interaction with cognate receptor. When the level of BMPER exceeds that of BMP4, BMPER may bind BMP4 and mask the binding sites of BMP4 for its receptor, resulting in BMP4 inhibition (155). Fibroblast growth factor 21 (FGF21) is one of the 22 FGF family members (96) and is primarily expressed in the liver and, to a lesser degree, in the thymus and adipose tissue (230,264). While the majority of FGF family proteins regulate cell proliferation and differentiation, FGF21 has been reported to mediate glucose and lipid metabolism (72, 144, 158). FGF21 interacts with FGF receptor 2 in adipocytes, resulting in activation of the ERK1/2 and Akt signaling pathways (138, 158, 219, 343). These signaling pathways are possibly responsible for FGF21-induced metabolic activities, although the exact mechanisms remain elusive. FGF21 has been reported to participate in the following metabolic activities: (1) stimulating insulin-independent glucose uptake in adipocytes (72, 158); (2) stimulating insulin expression in pancreatic β cells, potentiating insulin action, and reducing the level of plasma glucose (72, 158); (3) stimulating lipolysis in adipocytes and conversion of fatty acids to ketones in the liver (12, 72, 142); and (4) reducing plasma LDL while increasing plasma HDL (105, 133, 158). These observations suggest that FGF21 is a potential therapeutic agent for diabetes, lipid disorders, and obesity. Neuregulin 4 (NRG4), also known as heregulin 4 (HRG4), is found primarily in the pancreas and skeletal muscle (77). This is a plasma membrane-associated protein with a transmembrane domain when produced. The extracellular domain of this protein contains an epidermal growth factor-like motif. When synthesized, the protein is inserted into the plasma membrane and can be shed from the membrane into the extracellular space, possibly via proteinase-mediated cleavage (77). NRG4 can act on the protein tyrosine kinase-coupled receptor HER4 (or ErbB4) and induce receptor phosphorylation and activation, resulting in cell proliferation, neurite formation, and lineage determination of developing pancreatic islet cells (111, 120, 200, 201). Trefoil factor 3 (TFF3), also known as intestinal trefoil factor, is a soluble protein characterized by the presence of a trefoil motif (49, 103, 215). This protein was originally found in mucus-secreting goblet cells of the intestine (49, 103, 268), and has also been identified in the human hypothalamus and pituitary (247) as well as the mouse liver and urinary bladder (125). TFF3 contributes to the maintenance of mucosal integrity under physiological conditions and facilitates mucosal healing following mechanical and chemical injury (9,159,163,209,214,245,268,302-304,308,330). In vitro tests have demonstrated that TFF3 may enhance aggregation of intestinal mucin glycoproteins by establishing intermolecular bridges (268). This reaction results in the formation of a mechanically stable mucus layer on the intestinal epithelium. This layer protects the epithelium from chemical and mechanical injury. A recent study has demonstrated that TFF3 is activated in the liver of mice with ischemic stroke, protecting the ischemic brain from injury (198).



Potential roles of cytokines in regulating endocrine factor induction The induction of the endocrine protective factors in ischemic myocardial injury is likely an inflammation-dependent process. The inflammation-mediating factors cytokines may play a role in the induction of these factors. Inflammation starts with myocardial injury and death, involving various cell types including cardiomyocytes, leukocytes, fibroblasts, and vascular cells. Myocardial injury triggers a series of acute pathological events during the early period (approximately 1-7 days), including: (1) vasodilation to increase regional blood flow; (2) secretion of histamine from activated mast and endothelial cells to open the endothelial gap junctions, thereby increasing endothelial permeability and facilitating molecule and cell transport across the endothelial barrier (228, 298); (3) upregulation and release of cytokines such as IL1β, IL6, and TNF from injured cells and activated leukocytes to mediate inflammatory and protective responses (90-92,199); (4) upregulation and release of growth factors to stimulate cell proliferation and regeneration; and (5) leukocyte adhesion to the endothelium and migration to the injured and intact myocardium (182,342). These mechanisms facilitate the clearance of necrotic cells and promote myocardial protection and repair (30). The acute phase responses are followed by fibroblast proliferation and angiogenesis from approximately 1 to 3 weeks, processes largely controlled by growth factors and cytokines, contributing to granulation tissue formation and myocardial repair and also reinforcing the mechanical strength of the injured myocardium. These processes are referred to as sub-acute inflammatory responses and are accompanied with myocardial regeneration. The last phase of inflammation is fibrosis or scar formation due to fibroblast proliferation and excessive production of collagen matrix after approximately 3 weeks— a phase referred to as chronic inflammation. The chronic processes establish a strong fibrotic structure to replace the necrotic myocardium. In addition to regional inflammatory processes, global inflammation occurs in response to ischemic myocardial injury (30, 156, 263). The liver (199) and kidney (4, 237, 263) are often inflamed in myocardial ischemia, characterized by pathological changes as described above, but usually with a lower level of inflammation compared to that in the ischemic myocardium. Ischemic myocardial injury also causes activation and mobilization of splenic monocytes to the circulation and ischemic site, enhancing inflammatory responses (298). These global processes are likely induced and controlled by upregulated cytokines. Ischemic myocardial injury in both humans and animal models is associated with increased circulating cytokines, including IL1β, IL6, and TNF (15,24,64,90-92,199). Other cytokines may also be upregulated in ischemic myocardial injury, but have not been systematically identified. Cytokines may activate leukocyte and endothelial adhesion molecules, which in turn promote leukocyte adhesion to the endothelium, facilitating leukocyte extravasation and migration (263). Cytokines can also

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stimulate endothelial production of histamine, a substance increasing endothelial permeability and facilitating leukocyte infiltration. The infiltrating leukocytes are capable of upregulating and secreting additional cytokines that further enhance global inflammation (229), a critical process activating transsystem protective mechanisms. The circulating cytokines upregulated in global inflammation possibly stimulate the expression of endocrine protective factors from remote organs, thereby supporting myocardial survival and repair. A fundamental question is how cytokines exert such an effect. Here, we discuss possible mechanisms by using selected liver-derived cardioprotective proteins as examples. Cytokines can activate a number of transcription factors, including cJun, AP1, NFκB, STAT1, STAT2, STAT3, STAT4, STAT5, and/or STAT6 (267), through the mediation of cognate signaling networks as discussed in the sections above. The genes of three liver-derived cardioprotective proteins, including AGP2, FGF21, and TFF3, contain consensus binding site(s) for selected cytokine-induced transcription factors (267). The AGP2 gene promoter region contains binding sites for STAT1 (3 binding sites in humans and 2 in mice), STAT2 (1 in humans), STAT3 (1 in humans), STAT4 (1 in humans), STAT5A (1 in humans), STAT5B (1 in humans), and STAT6 (1 in humans) (267). The FGF21 gene promoter region contains binding sites for AP-1 (1 binding site in mice), cJun (1 in humans, 1 in mice), STAT3 (6 in humans, 1 in mice), STAT5A (1 in humans, 1 in mice), and STAT5B (5 in humans) (267). The TFF3 gene promoter region contains binding sites for AP1 (2 binding sites in humans, 2 in mice), cJun (1 in humans, 1 in mice), NFκB (3 in humans), STAT1 (1 in mice), and STAT3 (3 in humans, 2 in mice) (267). These observations suggest that selected cytokines may induce expression of the AGP2, FGF21, and TFF3 genes, providing a genetic basis for cytokine-mediated induction of endocrine cardioprotective proteins. However, the exact cytokines have not been identified. A screening strategy should be used to identify cytokines responsible for the induction of an endocrine cardioprotective factor. Among the five identified liver-derived cardioprotective factors, the BMPER and NRG4 genes do not contain consensus binding sites for the transcription factors named above (267). The inducing factors and transcription factors for BMPER and NRG4 expression remain to be identified. It is important to note that the transcription factors listed above may be directly involved in protective processes against ischemic injury. For instance, STAT5 is activated in cardiomyocytes in response to remote ischemic preconditioning and potentially contributes to ischemic myocardial protection in the human (126). Furthermore, factors other than cytokines may activate transcription factors cited above. For instance, growth factors, such as FGF and VEGF, may activate cJun and AP1 through the MAPK signaling networks (117, 195) and thereby serve as potential mediators for the trans-system protective mechanisms. However, these growth factors may not be upregulated as early as selected cytokines in response to ischemic myocardial injury and thus may contribute to latephase activation of the trans-system protective mechanisms.

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Induction of systemic cell mobilization In addition to upregulation and secretion of endocrine protective proteins as described above, another trans-system protective mechanism is cell mobilization from remote organs in response to ischemic myocardial injury. To date, three organ systems have been found to mobilize cells into the circulatory system in response to ischemic myocardial injury—the liver (199), bone marrow (76, 78, 169, 232, 255, 284, 300), and spleen (298). Mobilized cells may home to the ischemic myocardium, promoting myocardial survival, repair, and/or regeneration. Here, cell mobilization processes and regulatory mechanisms are discussed with a focus on the role of selected cytokines.

Characterization of cell mobilization in ischemic myocardial injury Ischemic myocardial injury induces mobilization of hepatic cells, including hepatocytes and biliary epithelial cells, into the circulatory system in the mouse model of myocardial ischemia/reperfusion injury. Circulating hepatic cells have been found from day 3 to 10 with a peak circulating hepatic cell population about 2% in reference to the leukocyte population at day 5 following ischemic myocardial injury, while few circulating hepatic cells are found in sham control mice (Fig. 3). The circulating hepatic cells can be tracked by using a transgenic mouse model with albumin gene promoterdriven, Cre recombinase-controlled, liver-specific expression of enhanced yellow fluorescent protein or EYFP (CreAlb;Stopflox -EYFP, where “Stop” represents a gene sequence that suppresses EYFP expression in the absence of Cre recombinase) (199). In this model, hepatocytes and biliary epithelial cells, which express EYFP (Fig. 4), can be tracked in the circulation and remote organs. Other hepatic and/or remote cell types may also be mobilized in response to ischemic myocardial injury, but cannot be identified in this model because of the lack of cell-specific markers. Mobilized hepatic cells potentially contribute to myocardial protection and repair. In addition to the liver, the bone marrow can discharge hematopoietic cells, including hematopoietic stem and progenitor cells, into the circulatory system at an increased rate in response to ischemic myocardial injury (76,78,169,232,255, 284, 300). These cells can home to the ischemic myocardium and release cytokines and growth factors, enhancing myocardial protection and repair. In particular, mobilized bone marrow cells include endothelial progenitor cells, which can promote endothelial cell formation and angiogenesis (284). Several soluble factors, including granulocyte colony stimulating factor (75, 204, 240, 283, 300, 307, 331), stromal cellderived factor 1 (8, 47, 113, 270), and vascular endothelial growth factor (7), have been identified as mediators for bone marrow cell mobilization and/or homing. These factors can be upregulated and released from injured myocardial cells and activated leukocytes, serving as endocrine messengers to promote bone marrow cell mobilization and homing.




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Characterization of the Alb-Cre;Stopflox -EYFP mouse model. (A) Expression of EYFP (green) in a liver specimen from an Alb-Cre;Stopflox -EYFP mouse. H: hepatocyte. BE: biliary epithelial cell. Red: cytokeratin-19, an epithelial cell marker expressed in biliary epithelial cells. (B) Expression of CD45 (red) in periductular cells of a liver specimen from an Alb-Cre;Stopflox -EYFP mouse. Blue: cell nuclei for both panels. Scale: 100 μm (199).

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Induction of bone marrow cell mobilization has been considered a potential treatment strategy for myocardial infarction. Furthermore, ischemic myocardial injury causes mobilization of splenic monocytes to the circulation and ischemic site to regulate inflammation and wound healing (298). Bone marrow and splenic cell mobilization has been well documented (75,78,169,232,240,255,284,298,300) and will not be further discussed here.


ischemic myocardium to promote myocardial protection and repair by direct delivery of protective factors. These cells may also participate in other reparative processes during myocardial injury and recovery, but information is incomplete at this time. Here, the cardioprotective action of the myocardial ischemia-induced endocrine factors and the potential roles of the mobilized hepatic cells in myocardial protection are discussed.

Role of IL6 in regulation of hepatic cell mobilization An important aspect of this research topic is how hepatic cells are mobilized in response to ischemic myocardial injury. Hepatic cells are organized into a parenchymal structure with the aid of extracellular matrix and cell-cell interaction molecules. To mobilize hepatic cells, the extracellular matrix and cell-cell interaction molecules must be degraded or disrupted. While it remains unclear how the cell-cell interaction molecules are disrupted, a recent study has provided insights into the mechanism of extracellular matrix degradation in the liver (199). This process begins with upregulation and release of cytokines from the ischemic myocardium. One of the cytokines, IL-6, after being released into the circulation, can activate circulating leukocytes, resulting in leukocyte extravasation in the liver (Fig. 5) (199). The role of IL-6 in regulating leukocyte transmigration has been confirmed by using an IL-6−/− mouse model with or without administration of recombinant IL6. IL-6−/− mice exhibit significantly reduced leukocyte transmigration, whereas administration of recombinant IL-6 reestablishes such a process. The density of the liverretained leukocytes peaks at 5 days in wild-type mice following ischemic myocardial injury (about sixfold higher than that in sham control mice) and is reduced subsequently (199). The liver-retained leukocytes upregulate and release MMP2, a proteinase that degrades collagen and other matrix components, resulting in liberation of hepatic cells in the vicinity of the liver-retained leukocytes. As observed by immunofluorescence microscopy, hepatic cells are discharged into the central vein in cell clusters, each associated with one or more leukocytes (Fig. 5D), supporting the notion that leukocytes mediate hepatic cell mobilization (199). Once in the vena cava, leukocytes are dissociated from the hepatic cell clusters.

Implementation of Trans-System Protective Mechanisms The trans-system protective mechanisms are implemented through upregulation and secretion of endocrine protective factors and mobilization of selected cell types from selected organs in ischemic myocardial injury as known to date. The protective factors and mobilized cells can access the ischemic myocardium via the circulatory system. The protective factors can activate various signaling networks in cardiomyocytes as well as other myocardial cell types, mediating cell survival and reparative processes. The mobilized cells may home to the

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Endocrine protection against ischemic myocardial injury The myocardial ischemia-induced hepatic proteins AGP2, BMPER, FGF21, NRG4, and TFF3 elicit profound protective actions against myocardial injury. These hepatic proteins are upregulated from 12 h to 5 days after myocardial ischemia (196). As myocardial cell death occurs during this period (196), these proteins may suppress cell death and support myocardial survival. The expression of these hepatic proteins is associated with an increase in their serum levels (196), supporting an endocrine mechanism for myocardial protection. The cardioprotective role of the hepatic proteins has been evaluated by using a siRNA-based partial loss-of-function model. Silencing one of the five hepatic protein genes by systemic administration of a specific siRNA intensified myocardial infarction, and silencing all five genes furthered the infarction intensification impact (196). These observations support the cardioprotective role of the upregulated hepatic proteins. However, these proteins are not upregulated during the early hours when myocardial injury occurs. Thus, it is necessary to provide protective proteins to the ischemic myocardium during the early period of ischemia, enhancing the effectiveness of protection. Indeed, administration of a single hepatic protective protein immediately following myocardial ischemia significantly reduced acute myocardial infarction, and administration of all five hepatic proteins in combination further enhanced the early cardioprotective effect (196). Administration of liver-derived protective proteins is also effective for long-term mitigation of myocardial infarction (Fig. 6) and improvement of left ventricular dp/dt and fractional shortening (Fig. 7). These observations suggest a potential cardioprotective strategy by using myocardial ischemia-induced hepatic proteins. A fundamental question is how a liver-derived protein protects the ischemic myocardium from injury. A recent investigation has provided experimental evidence to address the mechanism of FGF21-mediated cardioprotective action (197), while other liver-derived cardioprotective proteins remain to be investigated. FGF21 interacts potentially with all known protein tyrosine kinase-coupled FGF receptors (FGFRs), including FGFR1, FGFR2, FGFR3, and FGFR4, but preferentially binds to FGFR1 (19,343). The mouse cardiomyocyte expresses FGFR1 and FGFR3, but not FGFR2 and FGFR4 (197). FGF21 binds primarily to cardiomyocyte FGFR1, inducing phosphorylation of FGFR1 as well as several




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Figure 5 Leukocyte migration into the liver parenchyma in myocardial ischemia and the role of IL-6 in mediating leukocyte migration. (A) Fluorescence micrographs showing the lack of CD45-positive leukocytes (red) in the liver parenchyma of an Alb-Cre;Stopflox -EYFP mouse with sham operation at day 5. Panel A2 is a magnified image of the selected area in A1 (white rectangle). (B) CD45-positive leukocytes (red) retained in the liver parenchyma of an Alb-Cre;Stopflox -EYFP mouse with 5-day myocardial ischemia. Panel B2 is a magnified image of the selected area in B1. (C) CD45-positive leukocytes (red) with coexpression of MMP2 (green) in the liver parenchyma of a C57BL/6J mouse with 5-day myocardial ischemia. (D) Association of CD45-positive leukocytes (red) with mobilized EYFP-positive hepatic cells (green) within a central vein of the liver of an Alb-Cre;Stopflox -EYFP mouse with 5-day myocardial ischemia. Panel D2 and D3 are magnified images of the left and right white rectangles, respectively, from D1. (E) Fluorescence micrographs showing the lack of CD45-positive leukocytes (red) in the liver of an Alb-Cre;Stopflox -EYFP;IL6−/− mouse with 5-day myocardial ischemia. Panel E2 is a magnified image of the selected area in E1. (F) CD45-positive leukocytes (red) retained in the liver parenchyma of an Alb-Cre;Stopflox -EYFP;IL6−/− mouse with 5-day myocardial ischemia with IL-6 administration. Panel F2 is a magnified image of the selected area in F1. For panel A, B, D-F, the green color represents EYFP. For panel A-F, the blue color is for cell nuclei and the scale bars are 10 μm. (G) Graphic representation of the relative density of CD45-positive leukocytes migrated into the liver parenchyma of mice with sham-operation (open circles) and myocardial ischemia (solid circles) by fluorescence microscopy. Means and SDs are presented (P < 0.001 for changes in myocardial ischemia by ANOVA, n = 6 each time). Specimens at time zero were prepared from healthy mice. (H) Influence of IL6 on CD45-positive leukocyte migration into the liver parenchyma of Alb-Cre;Stopflox -EYFP (Cre-EYFP) and Alb-Cre;Stopflox -EYFP;IL6−/− (IL6−/− ) mice with sham-operation or myocardial ischemia. In panel G and H, the fraction of liver-retained CD45-positive leukocytes was calculated with reference to the total liver cells. (I) Flow cytometry analysis of liver cells derived from Alb-Cre;Stopflox -EYFP mice with sham operation or myocardial ischemia at day 5, showing CD45-positive leukocyte retention in the liver parenchyma in myocardial ischemia (199).


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AZAN-stained left ventricular sections from mice with ischemic myocardial injury administered with PBS or hepatic proteins, including AGP2, BMPER, FGF21, NRG4, and TFF3, showing the cardioprotective effect of the liver-derived proteins. Scale bar: 1 mm (196).

intracellular signaling molecules, including phosphoinositide 3-kinase (PI3K) p85, Akt1, and Bcl-XL/Bcl-2-associated death promoter (BAD) (197). A transmembrane protein known as β Klotho mediates the binding of FGF21 to FGFR1. β Klotho gene silencing by siRNA treatment caused a decrease in FGF21 interaction with FGFR1, attenuating the relative level of FGFR1 phosphorylation in the presence of FGF21 (197). PI3K is a kinase that phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2 ) to form phosphatidylinositol (3,4,5)-triphosphate (PIP3 ), a lipid molecule recruiting Akt1 to the cell membrane. PIP3 can also activate the protein kinase 3-phosphoinositide dependent protein kinase 1 (PDK1), which in turn phosphorylates Akt1. Phosphorylated Akt1 induces phosphorylation of BAD, thereby

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mitigating mitochondria-mediated cell death. Further investigations have demonstrated that silencing of the FGFR1, PI3K p110, or Akt1 gene by siRNA treatment dampens the protective effect of FGF21 (Fig. 8), suggesting a role for the FGFR1-PI3K-Akt1 signaling network in regulating FGF21dependent cardioprotective action. The function of BAD depends on the state of phosphorylation (61,117,197). When dephosphorylated, BAD promotes cell apoptosis by sequestering the antiapoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra large (Bcl-XL), rendering the pro-apoptotic factors Bcl-2 homologous antagonist/killer (BAK) and Bcl-2-associated X protein (BAX) more active (46, 61, 337). BAX and BAK are involved in pore formation in the mitochondrial outer membrane, allowing cytochrome C to escape from the mitochondria to the cytosol. Cytochrome C interacts with apoptotic protease activating factor 1 (Apaf1), inducing recruitment of caspase 9 to form a cytochrome C/Apaf-1/caspase 9 complex. This complex is referred to as apoptosome, a structure that cleaves pro-caspase 3 into caspase 3, an effector proteinase causing protein degradation and apoptosis (106, 168). When phosphorylated, BAD loses its apoptosis-promoting capability by releasing Bcl-2 and Bcl-XL, which suppress cell apoptosis (61). This is an acute protective mechanism observed during the early period of myocardial ischemia without the involvement of de novo gene expression. It is expected that this may not be the only mechanism mediated by FGF21. As discussed above, FGF21 can induce PI3K-Akt1 signaling, a process resulting in activation of cAMP response elementbinding protein (CREB) (74), a transcription factor causing de novo mitogen gene expression. FGF21 can also cause activation of the mitogen-activated protein kinase (MAPK) signaling network. These gene regulatory processes likely augment and prolong the cardioprotective effect of FGF21.

Potential cardioprotective action of mobilized hepatic cells Hepatic cell mobilization is a process activated in response to ischemic myocardial injury and is potentially involved in myocardial protection and repair. An important line of supporting evidence is that transplantation of hepatic cells from donor mice with acute myocardial ischemia, but not from sham control mice, into the circulation of recipient mice significantly mitigates acute myocardial infarction (202). A question is how the mobilized hepatic cells protect the ischemic myocardium from injury. One possible action is hepatic cell homing to the ischemic myocardium, secreting cardioprotective factors that support myocardial survival and repair as discussed in the sections above. Hepatic cells have been found in the ischemic myocardium as observed in the Cre-Alb;Stopflox -EYFP mouse model that expresses hepatic cell-specific EYFP (Liu et al., unpublished data), but it remains untested whether hepatic cells deliver cardioprotective factors to the ischemic myocardium and what factors are delivered. Nonetheless, these preliminary observations




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point to a hypothetical theory—hepatic cell mobilization may represent a naturally evolved trans-system mechanism that is activated in response to ischemic myocardial injury for myocardial protection and repair. However, it is challenging to confirm this theory because of the lack of loss-of-hepatic cell mobilization and loss-of-hepatic cell homing models. Establishment of any such model will provide concrete evidence to support the theory. An important observation is that mobilized hepatic cells are only found in the vena cava segment from the liver to the right heart, right and left ventricles, and ischemic myocardium, but not in the peripheral systemic arteries and veins (202). These observations suggest that the mobilized hepatic cells are possibly disintegrated in the high fluid shear stress environment of the systemic arterial system. Indeed, isolated mouse hepatocytes undergo rapid disintegration when subject to an in vitro culture-medium flow with arterial fluid shear stress (Liu et al., unpublished data). This process enables rapid release of hepatic cytoplasmic and nuclear contents into the circulation. These contents may include cardioprotective factors, as administration of liver extract from donor mice with acute myocardial ischemia, but not from sham control mice, mitigates acute myocardial infarction (202). In addition, administration of myocardial ischemia-conditioned liver extract causes a rapid increase in arterial blood pressure (Liu et al., unpublished data), suggesting the presence of vasoconstrictors. This response may represent a protective mechanism against blood pressure reduction in the event of heart failure. Thus, rapid disintegration of mobilized hepatic cells may represent another mechanism for protecting the ischemic myocardium from injury. However, a complete database of hepatic cell contents beneficial or harmful to myocardial protection remains to be established.


Significance of Trans-System Protective Mechanisms Ischemic myocardial injury activates regional protective mechanisms, including upregulation and/or release of paracrine factors and myocardial regeneration from cardiac resident stem cells. Given the presence of these regional protective mechanisms, a fundamental question is why a mammalian organism evolves trans-system mechanisms for myocardial protection. A possible reason is that the protective capacity of the regional mechanisms is limited and, thereby, trans-system mechanisms are established to assist in myocardial protection and repair. The multiple regional and transsystem protective mechanisms may act in coordination and synergy to maximize the protective effects, ensuring the survival of the heart as well as the entire organism. These observations and analyses suggest a theory that, while regional protective mechanisms are established for each organ, a set of core trans-system protective mechanisms is evolved to support selected organs in the event of injury by exploitation, a process employed for evolutionary development (36). The bone marrow, spleen, liver, and adipose tissue are organs known to harbor the trans-system protective mechanisms. This theory is supported by the observations that FGF21 and TFF3 are upregulated in the liver in response to either experimental myocardial or cerebral ischemia, contributing to myocardial and neuronal protection, respectively (196, 198, Liu et al., unpublished data), in spite of the activation of various regional protective mechanisms. However, other liverderived protective factors, including AGP2, BMPER, and NRG4, contribute to myocardial protection but not to neuronal protection (196, Liu et al., unpublished data), suggesting the presence of organ-dependent trans-system protective

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Figure 8 Influence of siRNA-mediated FGFR1, β-Klotho, PI3K p110, or Akt1 gene silencing on the degree of myocardial infarcts. (A) AZAN-stained left ventricular sections from FGF21−/− mice administered with a control, FGFR1, β-Klotho, PI3K p110, or Akt1 siRNA (siRNA injected into the myocardium at 3 days prior to myocardial ischemia/reperfusion injury, specimens collected at 5 days following myocardial injury). These mice were administered intravenously with recombinant FGF21 immediately following myocardial injury for 3 days with a 12 hr interval to establish FGF21-based myocardial protection. Scale bar: 1 mm. (B) Graphic representation of the influence of siRNA-mediated FGFR1, β-Klotho, PI3K p110, or Akt1 gene silencing on the degree of myocardial infarcts at day 5. Means and SDs are presented (n = 7) (197).

mechanisms. When an endocrine protective factor, such as FGF21, is upregulated in the liver in response to myocardial ischemia, it is not expressed in the ischemic myocardium (197). Likewise, a paracrine protective factor expressed in the ischemic myocardium, such as VEGF (154, 181, 192), is not upregulated in the liver (202). It seems that each organ system may only establish necessary regional protective mechanisms that are not involved in the core trans-system protective mechanisms. Additional necessary protective mechanisms are acquired from the trans-system core by exploitation. Such a developmental strategy avoids unnecessary duplication of the same set of required protective machineries for each organ system, a phenomenon consistent with the principle of cost

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minimization during evolution. However, this theory remains to be tested. It is now becoming clear that multiple paracrine and endocrine factors and signaling networks are involved in myocardial protection and repair. There is unlikely a single factor that prepares the heart to maximal protection. The significance of the multi-factor actions is to ensure maximal protection of the ischemic heart from all possible aspects. This point is well supported by the observation that administration of the liver-derived protective factors AGP2, BMPER, FGF21, NRG4, and TFF3 in combination is more effective than administration of a single factor from this group for alleviating ischemic myocardial injury (196). Furthermore,



myocardial or remote ischemic preconditioning and postconditioning, maneuvers activating all possible innate protective mechanisms, are more effective and reproducible for myocardial protection than administration of a single cardioprotective factor as demonstrated in a large number of experimental and clinical investigations (14,26,29,48,59,73,115-119,132,157, 166, 205, 211, 212, 226, 248, 288, 292, 294, 313, 315, 339, 344). Ischemic preconditioning is a procedure for inducing short ischemia/reperfusion episodes in the heart or a remote organ to attenuate the impact of a subsequent ischemic attack (29,73, 104, 115, 116, 118, 128, 211, 226, 280, 288, 314, 339), whereas postconditioning is to induce short ischemia/reperfusion episodes after a heart attack during an early coronary reperfusion intervention to reduce reperfusion injury (104,118,288,292,294,313,315,344). It is possible that these ischemic conditioning procedures may induce both regional and trans-system protective processes, upregulating various protective factors and activating protective cells, which in turn attenuate myocardial injury and promote myocardial repair and regeneration. However, this possibility remains to be tested. Another phenomenon relevant to ischemic conditioning is myocardial hibernation, a regulated adaptive reduction in myocardial contractility and metabolism in response to myocardial ischemia, thereby enhancing myocardial tolerance to ischemia (127,249,250,259). It is conceivable that the hibernation process is mediated by ischemia-induced factors that downregulate cardiomyocyte energetic activities. The concepts of myocardial preconditioning, postconditioning, and hibernation have been reviewed extensively in the citations above. As little information is available about the trans-system protective factors and cells involved in myocardial preconditioning, postconditioning, and hibernation, these topics will not be further discussed here.

Perspectives, Challenges, and Future Work A mammalian organism evolves with complex regional and trans-system protective mechanisms that are activated in response to ischemic myocardial injury and exploited to protect the heart from injury. The regional protective mechanisms involve paracrine factors and resident stem/progenitor cells, supporting myocardial survival, repair, and regeneration. The trans-system protective mechanisms involve selected systems, including the injured heart, circulation, and remote organs such as the bone marrow, spleen, liver, adipose tissue, and potentially others (to be determined), and act in coordination and synergy with the regional mechanisms to maximize the cardioprotective effect. Preliminary evidence has pointed to the necessity of the trans-system mechanisms for effective myocardial protection. The discovery of the transsystem mechanisms may lead to a new paradigm of research in myocardial protection, repair, and regeneration. The trans-system theory may be extended to other organs to explore similar protective mechanisms in injury. It is expected



that a generalized theory may be established and used to understand the naturally evolved protective processes from a global point of view and develop treatment strategies for ischemia- and other injury-induced disorders. To date, the liver and adipose tissue have been identified as remote systems that produce endocrine cardioprotective factors in response to ischemic myocardial injury, including AGP2, BMPER, FGF21, NRG4, and TFF3 from the liver (196) and FGF21 from the adipose tissue (197). It is possible that other organs are involved to produce additional endocrine factors for myocardial protection and repair. Previous investigations have suggested a large number of cardioprotective factors, including adipocytokines (leptin, adiponectin, apelin, and visfatin) (207, 290, 301, 320), erythropoietin (41), FGF1 (117), FGF2 (152,336), insulin (95,165), IGF1 (40), humanin (180, 227), frizzled related protein 2 (121), TGFβ (183, 184), urocortin (63, 274), protein C (318), and leukemia inhibitory factor (346). It will be interesting to test whether these factors include endocrine cardioprotective mediators. However, to completely understand the naturally evolved protective mechanisms, it is necessary to develop a database containing paracrine and endocrine cardioprotective factors from all possible organ systems. Such a database may be established by whole-organism genomic and proteomic profiling analyses coupled with functional screening tests. Similar strategies may be used to identify protective factors activated in response to various types of injury in other organ systems. This information is critical to understanding the nature-established protective mechanisms and developing effective protective strategies against injuries. Challenging tasks for this work are identification of factors that induce upregulation and release of the protective factors and elucidation of the mechanisms of protective factor action. In addition to paracrine and endocrine protective factors, protective cell types, such as bone marrow, splenic, and hepatic cells, are mobilized to participate in protection and repair of the ischemic myocardium or potentially other injured organs. Additional trans-system cell types may be mobilized in response to injury and involved in protective processes. Mobilized cells from a selected organ may be identified and tracked by using a cell-specific transgenic marker, such as the albumin gene promoter-activated, Cre recombinase-induced EYFP marker for tracking mobilized hepatic cells (199). A challenging task for this model is to identify cell-specific gene promoters. The majority of gene promoters may not be specific to a selected cell type, rendering it difficult to precisely define the cell types expressing a selected gene. A more challenging task is to elucidate the mechanisms of the protective action of each mobilized cell type. While mobilized cells may home to the ischemic myocardium or other injured organs to locally deliver protective factors, these cells may participate in other reparative and regenerative processes. Because of the presence of multiple resident and engrafted protective cell types in an injured tissue, it is often difficult to pin down precisely the function of a selected cell type.

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It is necessary to develop technologies to overcome these difficulties.

Acknowledgements The authors thank Dr. Robert Linsenmeier from the Biomedical Engineering Department at Northwestern University for concrete suggestions to manuscript revision. Partial work cited in the article was supported by the National Science Foundation.

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Cardioprotection against experimental myocardial ischemic injury using cornin.

reperfusion injury.

Quantification of myocardial ischemic injury.

Neuroprotective Mechanisms of Taurine against Ischemic Stroke.

Myocardial Protection: The Science and Pathophysiology of Myocardial Ischemic Injury.

Effects of morphine and sufentanil preconditioning against myocardial ischemic-reperfusion injury in rabbits.

Molecular targets for anti-oxidative protection of green tea polyphenols against myocardial ischemic injury.

Protective effect of erythropoietin against myocardial injury in rats with sepsis and its underlying mechanisms.

Editorial: Molecular Mechanisms Protecting against Tissue Injury.

Coronary venous hypertension: a potentiator of myocardial ischemic injury.

Effects of arterial hypertension on myocardial recovery after ischemic injury.

Reduction of ischemic injury by nitroglycerin during acute myocardial infarction.

Changes in ultrasonic attenuation indicative of early myocardial ischemic injury.

CPK isoenzymes in evaluation of myocardial ischemic injury.

A Role for Photobiomodulation in the Prevention of Myocardial Ischemic Reperfusion Injury: A Systematic Review and Potential Molecular Mechanisms.

Amitriptyline pharmacologically preconditions rat hearts against cardiac ischemic-reperfusion injury.

Hyperthermia-induced neuronal protection against ischemic injury in gerbils.

Septo-hippocampal deafferentation protects CA1 neurons against ischemic injury.

Non-Coding RNAs as Potential Neuroprotectants against Ischemic Brain Injury.

NFAT5 is protective against ischemic acute kidney injury.

reperfusion injury in spontaneously hypertensive rats.

Protective Role of Ramipril and Candesartan against Myocardial Ischemic Reperfusion Injury: A Biochemical and Transmission Electron Microscopical Study.

calcitonin gene-related peptide pathway.

mTOR Pathway.