Editorial Comment Cardiology 2015;131:107–108 DOI: 10.1159/000381180
Received: February 24, 2015 Accepted: February 24, 2015 Published online: April 18, 2015
The Relation between CD40 Ligand and Coronary Artery Disease Sevket Balta a Cengiz Ozturk b a
Department of Cardiology, Eskişehir Military Hospital, Eskişehir, and b Department of Cardiology, Gulhane Medical Faculty, Ankara, Turkey
© 2015 S. Karger AG, Basel 0008–6312/15/1312–0107$39.50/0 E-Mail [email protected] www.karger.com/crd
sCD40L can also be used to predict the risk of future cardiovascular disease in healthy women and the clinical outcomes in patients with acute coronary syndromes. Atherogenesis includes the participation of inflammatory pathways within cellular interactions, but it is still not known what mediates local communication between the major cell types within atherogenesis in vivo [2]. In a previous study, the authors aimed to investigate the role of CD40 signalling in atherogenesis [3]. They concluded that treatment with the antibody against mouse CD40L limited atherosclerosis in mice lacking the receptor for low-density lipoprotein which had been fed a high-cholesterol diet for 12 weeks. CD40L antibody also decreased the size of aortic atherosclerotic lesions and their lipid content. Furthermore, atheroma of mice treated with anti-CD40L antibody contained significantly fewer macrophages and T lymphocytes, and exhibited a reduced expression of vascular-cell adhesion molecule-1. These data are important as they suggest the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice [3]. A major role of the contact-dependent relation between CD40 and CD40L is the stimulus for atheromaassociated cells. Both soluble and contact-dependent mediators from T cells may be important for improving the outcome of common diseases. The involvement of the CD40 signalling pathway during atherogenesis may be crucial due to its regulation of antigen-specific T-cell responses to yield activation instead of tolerance. In addiDr. Sevket Balta Department of Cardiology, Eskişehir Military Hospital Vişnelik Mah., Atatürk Cd. TR–26020 Akarbaşı/Eskişehir (Turkey) E-Mail drsevketb @ gmail.com
Downloaded by: UCONN Storrs 198.143.38.1 - 1/27/2016 9:07:23 PM
Atherosclerosis is one of the most common fatal diseases worldwide. It has been known for many years that endothelial cells, smooth-muscle cells and macrophages play a major role in the process of atherosclerosis. The formation of atherosclerotic plaque is attributed to the infiltration of immune defence cells like macrophages and T lymphocytes, the proliferation of intimal cells of the arterial wall, the collection of lipids and the deposition of extracellular matrix components. Macrophage contents and the expression of tissue factors are associated with the rupture and instability of the atherosclerotic plaque [1]. In this respect, macrophages play an important role in the progression of atherosclerosis by exhibiting unique characteristics due to different stimuli and contributing to plaque instability, thrombus formation and remodeling. CD40 and its ligand (CD40L) were first discovered on the surface of activated T cells, but their presence on B cells, antigen-presenting cells, mast cells and platelets is also evident. The soluble form of CD40L (sCD40L) is derived mainly from activated platelets and contributes to the pathophysiology of atherosclerosis and atherothrombosis. Indeed, sCD40L has autocrine, paracrine and endocrine activities, and it enhances platelet activation, aggregation and platelet-leucocyte conjugation that may lead to atherothrombosis. It has even been suggested that it plays a pathogenic role in triggering acute coronary syndromes. Conversely, blockade of this pathway with anti-CD40L antibodies may prevent or delay the progression of atherosclerosis. Concentrations of
tion, the presence of functional CD40L on non-leucocytic cells associated with atherosclerotic lesions indicates a novel T-cell-independent route of inflammatory activation. These findings establish a potentially crucial role for CD40-CD40L interactions in prevalent human diseases [4]. Activation of T lymphocytes within the atherosclerotic vessel wall reveals the CD40L surface molecule; it is well known that this plays a major role in several immunological pathways. Functional CD40 and CD40L are coexpressed by vascular endothelial cells, smooth-muscle cells and macrophages in vitro as well as in situ in atherosclerotic lesions. It has been found that the majority of macrophages, especially foam cells, are positive for both CD40 and CD40L [5]. In the latest issue of Cardiology, Yuan et al. [6] investigate the role of sCD40L in the formation of foam cells. They conclude that sCD40L stimulation promotes foam cell formation. In this respect, further studies will confirm the importance of sCD40L in atherosclerosis as a target for the treatment of this disease. The expression of several genes was analyzed in cells treated with sCD40L, including adipocyte enhancer-binding protein 1. A role for CD40-CD40L interactions has been displayed in atherosclerosis, and such interactions are known to destabilize atherosclerotic plaques by inducing the expression of cytokines, chemokines, growth factors, matrix metalloproteinases and pro-coagulant factors. The CD40CD40L interaction has also been implicated in immune
system disorders, and CD40L and its receptor CD40 participate in numerous inflammatory pathways that contribute to multiple pathophysiological processes [7]. Recent studies have suggested that CD40-CD40L interactions regulate oxidative stress and affect various signalling pathways in both the immunological and cardiovascular systems [8]. The role and regulation of CD40-CD40L-mediated oxidative signalling in immune and non-immune cells could facilitate the development of therapeutics to target diverse inflammatory diseases [8]. As a conclusion, this recent study [6] found that sCD40L significantly increases lipid deposition and foam cell formation via the activation of scavenger receptors. It is an interesting study, but should have detailed the conditions more. It is important to note that adipogenesis and the formation of foam cells occur via different pathways. The cholesterol contents in the cells need to be normalized by cell numbers. Disruption of the ligation between CD40 and CD40L by a blocking anti-CD40 antibody was shown to inhibit foam cell formation induced by sCD40L. This conduction needs to be evaluated in future human studies.
Disclosure Statement There are no conflicts of interest.
References
108
4 Mach F, Schönbeck U, Libby P: CD40 signaling in vascular cells: a key role in atherosclerosis? Atherosclerosis 1998;137(suppl):S89–S95. 5 Häkkinen T, Karkola K, Ylä-Herttuala S: Macrophages, smooth muscle cells, endothelial cells, and T-cells express CD40 and CD40L in fatty streaks and more advanced human atherosclerotic lesions. Colocalization with epitopes of oxidized low-density lipoprotein, scavenger receptor, and CD16 (Fcγ). Virchows Arch 2000;437:396–405.
Cardiology 2015;131:107–108 DOI: 10.1159/000381180
6 Yuan M, Fu H, Ren L, Wang H, Guo W: Soluble CD40 ligand promotes macrophage foam cell formation in the etiology of atherosclerosis. Cardiology 2015;131:1–12. 7 Zhang B, Wu T, Chen M, Zhou Y, Yi D, Guo R: The CD40/CD40L system: a new therapeutic target for disease. Immunol Lett 2013;153: 58–61. 8 Rizvi M, Pathak D, Freedman JE, Chakrabarti S: CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease. Trends Mol Med 2008;14:530–538.
Balta/Ozturk
Downloaded by: UCONN Storrs 198.143.38.1 - 1/27/2016 9:07:23 PM
1 Tuttolomondo A, Di Raimondo D, Pecoraro R, Arnao V, Pinto A, Licata G: Atherosclerosis as an inflammatory disease. Curr Pharm Des 2012;18:4266–4288. 2 Pamukcu B, Lip GYH, Snezhitskiy V, Shantsila E: The CD40-CD40L system in cardiovascular disease. Ann Med 2011;43:331–340. 3 Mach F, Schönbeck U, Sukhova GK, Atkinson E, Libby P: Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998;394:200–203.
Received: February 24, 2015 Accepted: February 24, 2015 Published online: April 18, 2015
The Relation between CD40 Ligand and Coronary Artery Disease Sevket Balta a Cengiz Ozturk b a
Department of Cardiology, Eskişehir Military Hospital, Eskişehir, and b Department of Cardiology, Gulhane Medical Faculty, Ankara, Turkey
© 2015 S. Karger AG, Basel 0008–6312/15/1312–0107$39.50/0 E-Mail [email protected] www.karger.com/crd
sCD40L can also be used to predict the risk of future cardiovascular disease in healthy women and the clinical outcomes in patients with acute coronary syndromes. Atherogenesis includes the participation of inflammatory pathways within cellular interactions, but it is still not known what mediates local communication between the major cell types within atherogenesis in vivo [2]. In a previous study, the authors aimed to investigate the role of CD40 signalling in atherogenesis [3]. They concluded that treatment with the antibody against mouse CD40L limited atherosclerosis in mice lacking the receptor for low-density lipoprotein which had been fed a high-cholesterol diet for 12 weeks. CD40L antibody also decreased the size of aortic atherosclerotic lesions and their lipid content. Furthermore, atheroma of mice treated with anti-CD40L antibody contained significantly fewer macrophages and T lymphocytes, and exhibited a reduced expression of vascular-cell adhesion molecule-1. These data are important as they suggest the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice [3]. A major role of the contact-dependent relation between CD40 and CD40L is the stimulus for atheromaassociated cells. Both soluble and contact-dependent mediators from T cells may be important for improving the outcome of common diseases. The involvement of the CD40 signalling pathway during atherogenesis may be crucial due to its regulation of antigen-specific T-cell responses to yield activation instead of tolerance. In addiDr. Sevket Balta Department of Cardiology, Eskişehir Military Hospital Vişnelik Mah., Atatürk Cd. TR–26020 Akarbaşı/Eskişehir (Turkey) E-Mail drsevketb @ gmail.com
Downloaded by: UCONN Storrs 198.143.38.1 - 1/27/2016 9:07:23 PM
Atherosclerosis is one of the most common fatal diseases worldwide. It has been known for many years that endothelial cells, smooth-muscle cells and macrophages play a major role in the process of atherosclerosis. The formation of atherosclerotic plaque is attributed to the infiltration of immune defence cells like macrophages and T lymphocytes, the proliferation of intimal cells of the arterial wall, the collection of lipids and the deposition of extracellular matrix components. Macrophage contents and the expression of tissue factors are associated with the rupture and instability of the atherosclerotic plaque [1]. In this respect, macrophages play an important role in the progression of atherosclerosis by exhibiting unique characteristics due to different stimuli and contributing to plaque instability, thrombus formation and remodeling. CD40 and its ligand (CD40L) were first discovered on the surface of activated T cells, but their presence on B cells, antigen-presenting cells, mast cells and platelets is also evident. The soluble form of CD40L (sCD40L) is derived mainly from activated platelets and contributes to the pathophysiology of atherosclerosis and atherothrombosis. Indeed, sCD40L has autocrine, paracrine and endocrine activities, and it enhances platelet activation, aggregation and platelet-leucocyte conjugation that may lead to atherothrombosis. It has even been suggested that it plays a pathogenic role in triggering acute coronary syndromes. Conversely, blockade of this pathway with anti-CD40L antibodies may prevent or delay the progression of atherosclerosis. Concentrations of
tion, the presence of functional CD40L on non-leucocytic cells associated with atherosclerotic lesions indicates a novel T-cell-independent route of inflammatory activation. These findings establish a potentially crucial role for CD40-CD40L interactions in prevalent human diseases [4]. Activation of T lymphocytes within the atherosclerotic vessel wall reveals the CD40L surface molecule; it is well known that this plays a major role in several immunological pathways. Functional CD40 and CD40L are coexpressed by vascular endothelial cells, smooth-muscle cells and macrophages in vitro as well as in situ in atherosclerotic lesions. It has been found that the majority of macrophages, especially foam cells, are positive for both CD40 and CD40L [5]. In the latest issue of Cardiology, Yuan et al. [6] investigate the role of sCD40L in the formation of foam cells. They conclude that sCD40L stimulation promotes foam cell formation. In this respect, further studies will confirm the importance of sCD40L in atherosclerosis as a target for the treatment of this disease. The expression of several genes was analyzed in cells treated with sCD40L, including adipocyte enhancer-binding protein 1. A role for CD40-CD40L interactions has been displayed in atherosclerosis, and such interactions are known to destabilize atherosclerotic plaques by inducing the expression of cytokines, chemokines, growth factors, matrix metalloproteinases and pro-coagulant factors. The CD40CD40L interaction has also been implicated in immune
system disorders, and CD40L and its receptor CD40 participate in numerous inflammatory pathways that contribute to multiple pathophysiological processes [7]. Recent studies have suggested that CD40-CD40L interactions regulate oxidative stress and affect various signalling pathways in both the immunological and cardiovascular systems [8]. The role and regulation of CD40-CD40L-mediated oxidative signalling in immune and non-immune cells could facilitate the development of therapeutics to target diverse inflammatory diseases [8]. As a conclusion, this recent study [6] found that sCD40L significantly increases lipid deposition and foam cell formation via the activation of scavenger receptors. It is an interesting study, but should have detailed the conditions more. It is important to note that adipogenesis and the formation of foam cells occur via different pathways. The cholesterol contents in the cells need to be normalized by cell numbers. Disruption of the ligation between CD40 and CD40L by a blocking anti-CD40 antibody was shown to inhibit foam cell formation induced by sCD40L. This conduction needs to be evaluated in future human studies.
Disclosure Statement There are no conflicts of interest.
References
108
4 Mach F, Schönbeck U, Libby P: CD40 signaling in vascular cells: a key role in atherosclerosis? Atherosclerosis 1998;137(suppl):S89–S95. 5 Häkkinen T, Karkola K, Ylä-Herttuala S: Macrophages, smooth muscle cells, endothelial cells, and T-cells express CD40 and CD40L in fatty streaks and more advanced human atherosclerotic lesions. Colocalization with epitopes of oxidized low-density lipoprotein, scavenger receptor, and CD16 (Fcγ). Virchows Arch 2000;437:396–405.
Cardiology 2015;131:107–108 DOI: 10.1159/000381180
6 Yuan M, Fu H, Ren L, Wang H, Guo W: Soluble CD40 ligand promotes macrophage foam cell formation in the etiology of atherosclerosis. Cardiology 2015;131:1–12. 7 Zhang B, Wu T, Chen M, Zhou Y, Yi D, Guo R: The CD40/CD40L system: a new therapeutic target for disease. Immunol Lett 2013;153: 58–61. 8 Rizvi M, Pathak D, Freedman JE, Chakrabarti S: CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease. Trends Mol Med 2008;14:530–538.
Balta/Ozturk
Downloaded by: UCONN Storrs 198.143.38.1 - 1/27/2016 9:07:23 PM
1 Tuttolomondo A, Di Raimondo D, Pecoraro R, Arnao V, Pinto A, Licata G: Atherosclerosis as an inflammatory disease. Curr Pharm Des 2012;18:4266–4288. 2 Pamukcu B, Lip GYH, Snezhitskiy V, Shantsila E: The CD40-CD40L system in cardiovascular disease. Ann Med 2011;43:331–340. 3 Mach F, Schönbeck U, Sukhova GK, Atkinson E, Libby P: Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998;394:200–203.
