Myocardial metabolism in diabetic cardiomyopathy: potential therapeutic targets.

ANTIOXIDANTS & REDOX SIGNALING Volume 22, Number 17, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/ars.2015.6305

FORUM REVIEW ARTICLE

Myocardial Metabolism in Diabetic Cardiomyopathy: Potential Therapeutic Targets Miranda M. Sung, Shereen M. Hamza, and Jason R.B. Dyck

Abstract

Significance: Cardiovascular complications in diabetes are particularly serious and represent the primary cause of morbidity and mortality in diabetic patients. Despite early observations of cardiac dysfunction in diabetic humans, cardiomyopathy unique to diabetes has only recently been recognized. Recent Advances: Research has focused on understanding the pathogenic mechanisms underlying the initiation and development of diabetic cardiomyopathy. Emerging data highlight the importance of altered mitochondrial function as a major contributor to cardiac dysfunction in diabetes. Mitochondrial dysfunction occurs by several mechanisms involving altered cardiac substrate metabolism, lipotoxicity, impaired cardiac insulin and glucose homeostasis, impaired cellular and mitochondrial calcium handling, oxidative stress, and mitochondrial uncoupling. Critical Issues: Currently, treatment is not specifically tailored for diabetic patients with cardiac dysfunction. Given the multifactorial development and progression of diabetic cardiomyopathy, traditional treatments such as anti-diabetic agents, as well as cellular and mitochondrial fatty acid uptake inhibitors aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose may not adequately target all aspects of this condition. Thus, an alternative treatment such as resveratrol, which targets multiple facets of diabetes, may represent a safe and promising supplement to currently recommended clinical therapy and lifestyle changes. Future Directions: Elucidation of the mechanisms underlying the initiation and progression of diabetic cardiomyopathy is essential for development of effective and targeted treatment strategies. Of particular interest is the investigation of alternative therapies such as resveratrol, which can function as both preventative and mitigating agents in the management of diabetic cardiomyopathy. Antioxid. Redox Signal. 22, 1606–1630.

Introduction

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ardiovascular disease (CVD) is the principal cause of morbidity and mortality among diabetic patients (38). Although diabetes-related heart failure (HF) was first observed more than 40 years ago (213, 219), it is only recently recognized that diabetics are predisposed to a distinctive cardiomyopathy that is independent of accompanying macro/ microvascular complications typically associated with this disease (16). Indeed, early epidemiological studies showed that independent of age, obesity, or dyslipidemia, diabetes alone was linked with a two-fold increased risk of HF in men and a five-fold increased risk in women (129). Further to this, diabetic patients also comprise 15%–20% of subjects in HF clinical trials (54), and there is evidence that diabetes itself is

an independent predictor of poor outcomes in HF (86, 235). The association between diabetes and cardiac dysfunction in humans is also supported by data from animal models, which demonstrate distinct diabetes-induced cardiac structural, metabolic, and functional changes (99, 122, 288). This specific cardiac phenotype has been defined as diabetic cardiomyopathy and is characterized by early impairment in diastolic function with development of cardiomyocyte hypertrophy, myocardial fibrosis, and cardiomyocyte apoptosis, all of which are in the absence of coronary artery disease (CAD), hypertension, or valvular dysfunction. Although the term ‘‘diabetic cardiomyopathy’’ is now an accepted clinical definition, making a formal diagnosis of diabetic cardiomyopathy remains difficult as what constitutes this condition remains vague and there is no widely accepted

Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Canada.

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MITOCHONDRIAL STRESS IN DIABETIC CARDIOMYOPATHY

diagnostic criteria. Although there is some uncertainty regarding the detailed, step-wise pathogenesis of this condition (223), the earliest signs of diabetic cardiomyopathy are left ventricular hypertrophy (LVH) and diastolic dysfunction in type 1 and type 2 diabetic (T1D and T2D) patients. Although not routinely performed in standard clinical echocardiograms, more rigorous methods of diagnostic echocardiography (65) demonstrate that early mild diastolic dysfunction occurs often in diabetic patients. In fact, impaired left ventricular (LV) relaxation and filling is evident in 21%–75% of asymptomatic diabetic patients who do not have overt CVD or microvascular complications (62, 272, 286, 289, 290), demonstrating that diabetic cardiomyopathy is not a rare condition (212). Moreover, diastolic dysfunction is also observed in rodent models of T1D and T2D (116, 216), in the absence of overt vascular dysfunction or atherosclerosis, suggesting a cardiac-specific response to diabetes. In agreement with this, abnormalities are also evident in cardiomyocytes isolated from T2D rats (88), providing further support that diabetes directly affects the cardiomyocyte. Although it is not entirely clear what initiates the early stages of diabetic cardiomyopathy, possible factors contributing to the development of diastolic dysfunction in diabetes include systemic insulin resistance and hyperglycemia (9), increased cardiac collagen deposition (180), altered cardiomyocytespecific glucose and lipid metabolism (14) and oxidative stress (115, 116, 216), as well as dysregulation of calcium (Ca2 + ) homeostasis (88). Whether these alterations occurring within the cardiomyocyte also contribute to a gradual progression of diabetic cardiomyopathy and the presence of systolic dysfunction (272, 276, 286) that may occur later in the pathogenesis of diabetic cardiomyopathy is currently unknown. Despite the complex and multifactorial pathophysiology of diabetic cardiomyopathy, it is becoming clear that alterations in cardiac energy substrate metabolism are critically involved. Since glucose utilization as a source of energy by the cardiomyocyte is impaired in diabetes (73) and there is an abundant supply of free fatty acids (FFAs), hearts from diabetics have dramatic changes in their metabolic profile (177, 269). As a result, the diabetic heart depends almost completely on fatty acid oxidation (FAO) for adenosine triphosphate (ATP) synthesis (83, 112). Although FAO rates are accelerated, the excess supply and subsequent uptake of lipids into the cardiomyocyte still appears to exceed FA

FIG. 1. Summary of mechanisms contributing to the development of diabetic cardiomyopathy.

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utilization, leading to elevated FA storage within the cardiomyocyte. It appears that accumulation of lipid precedes the cardiac dysfunction (177), suggesting that they contribute to the eventual decline in cardiac performance. Consistent with this, the combination of ectopic FA accumulation within the cardiomyocyte and the over-reliance on FAO, consequently, compromises mitochondrial respiratory function and leads to elevated reactive oxygen species (ROS) production by the mitochondria. This contributes to eventual mitochondrial damage (269), thus linking lipotoxicity, oxidative stress, and mitochondrial dysfunction (73). This is extremely important, as impaired mitochondrial function is a key pathophysiological trigger for the development of diabetic cardiomyopathy (124) and may thus represent the final common pathway, leading to cardiac dysfunction (Fig. 1). Although it is recognized that diabetes imposes an extra burden on the heart (due to alterations in cardiac energy metabolism and increased cardiomyocyte oxidative stress and apoptosis that is characteristic of this disease), current therapeutic options do not specifically target diabetes-induced cardiac dysfunction. Clinically, cardiac dysfunction is managed equally between diabetic and non-diabetic patients (67) with no specific therapy recommended at the preclinical stage of diabetic cardiomyopathy. Considering that the perturbations involved in the development of diabetic cardiomyopathy may contribute to the high cardiac mortality in this patient population (63, 89), it is essential to understand the mechanisms underlying this condition to improve disease management and reduce patient morbidity and mortality. As such, we will present evidence that demonstrates the presence of mitochondrial dysfunction in diabetes and how this contributes to the pathogenesis of diabetic cardiomyopathy as well as discuss potential therapeutic targets to prevent or manage this condition. Lastly, we will review exciting recent data supporting the application of metabolic modulators and the natural polyphenol resveratrol in the management of diabetes and discuss the potential use of these therapies in the specific treatment of diabetic cardiomyopathy. Alterations in Myocardial Metabolism and Mitochondrial Function in Diabetes

A growing body of evidence has shown that altered energy metabolism and mitochondrial dysfunction is present in

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hearts from patients with insulin resistance and diabetes (202, 224). It has been proposed that altered myocardial energy metabolism resulting from changes in energy substrate supply and utilization, as well as altered mitochondrial function, can ultimately impact cardiac function, leading to the development of diabetic cardiomyopathy (14, 24). Indeed, using magnetic resonance imaging and phosphorus-31-nuclear MR spectroscopy, Diamant et al. (66) showed that diastolic function was impaired and myocardial high-energy phosphate metabolism (as measured by the phosphocreatine [PCr]/ATP ratio) was significantly reduced in asymptomatic normotensive male patients (50–65 years old) with wellcontrolled and uncomplicated T2D compared with control subjects. These findings were confirmed by Clarke and colleagues (224), who showed that T2D patients with normal cardiac mass and function have impaired cardiac energy metabolism as evidenced by a > 30% reduction in PCr/ATP ratio. They also showed that myocardial functional and metabolic decreases were negatively correlated with plasma FFA concentration and positively correlated with plasma glucose in all subjects (224). Furthermore, using positron emission tomography (PET), it was shown that increased body mass index and impaired glucose tolerance were strongly correlated with increased myocardial oxygen consumption (MVO2), reduced cardiac efficiency, and increased myocardial FA metabolism (uptake and utilization) in young, obese, and insulin-resistant women (203). Together, these findings suggest that alterations in cardiac energetics and mitochondrial function occur early in the development of diabetic cardiomyopathy before the onset of overt cardiac dysfunction, thus supporting the concept that altered mitochondrial metabolism may be causative in this pathology. Although a link between impaired cardiac function/metabolism and T2D has been observed in humans, not all human studies have found significant changes in high energy phosphate metabolism or cardiac energy substrate metabolism in obese or diabetic patients (136, 215, 264, 270). However, these studies do not necessarily discount the role of altered mitochondrial metabolism in diabetic cardiomyopathy, as differences in sex, age, diet and lifestyle, endogenous myocardial fat content, and severity of hyperglycemia and diabetes may have influenced the results. Fortunately, this possible conflict as to whether or not cardiac energy substrate metabolism is altered in obese or diabetic patients may have been resolved by recent reports performing direct mitochondrial measurements on atrial tissue samples from diabetic patients. Specifically, Anderson et al. (4) demonstrated that permeabilized atrial myofibers from T2D individuals have significantly decreased capacity for glutamate and FAsupported respiration, as well as increased intra-myocardial triglycerides (TAG), compared with non-diabetic patients. In addition, diabetic patients had increased mitochondrial hydrogen peroxide (H2O2) emission, which may result from a reduced capacity of the thioredoxin 2 system in the mitochondria. Usually, this system neutralizes the natural production of H2O2 by mitochondria; however, when this antioxidant system is compromised, H2O2 production is unchecked and allowed to accumulate (243), thus interfering with mitochondrial and cellular functions. In addition to diabetic patients demonstrating increased mitochondrial H2O2 production, they also display chronically elevated levels of oxidative stress in atrial tissue as shown

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by increased levels of 4-hydroxy-2-nonenal (HNE)—and 3nitrotyrosine—modified proteins. Interestingly, both HNE and tyrosine nitrosylation are known to impair the activity of several complexes of the electron transport chain (ETC) found in the mitochondrial inner membrane and matrix (52), suggesting that impaired ETC activity may contribute to mitochondrial dysfunction. In addition, Montaigne et al. (182) showed, using isolated trabeculae from the atrial appendage, that diabetes was associated with a dramatic increase in myocardial oxidative stress. These authors also used electron microscopy to show that mitochondria from diabetic patients were smaller, had a reduced capacity to retain Ca2 + and reduced expression of mitochondrial fission protein (mitofusin-1), suggesting that there are changes in mitochondrial ultrastructure and dynamics that contribute to the development of cardiomyopathy (182). Furthermore, these impairments in mitochondrial function were associated with impaired contractility (182). Overall, the aforementioned human studies provide direct evidence demonstrating the presence of structural and functional deficiencies in cardiac mitochondria, increased oxidative stress, impaired Ca2 + handling, and myocardial lipid accumulation, all of which have been proposed to be important contributing mechanisms in the pathogenesis of diabetic cardiomyopathy. Since there are inherent limitations to performing mechanistic studies in humans, many of the insights into the underlying mechanisms responsible for diabetic cardiomyopathy have come from studying rodent models. Although rats/mice are relatively resistant to developing atherosclerosis and subsequent CAD, which is commonly found in humans with diabetes (119), this actually allows for more targeted dissection of pathways in the absence of confounding co-morbidities (148). Moreover, human studies of diabetic cardiomyopathy often exclude patients with ischemic heart disease, CAD, or hypertension in attempts to better understand the pathogenesis of diabetic cardiomyopathy in the absence of these confounding diseases (66). Consistent with the concept that diabetic cardiomyopathy is a distinct clinical entity, many of the findings in rodent models of obesity, insulin resistance, and diabetes mimic what has been observed in humans with these same pathologies. In addition, rodent models are amenable to genetic manipulation, allowing researchers to examine the role of specific proteins and signaling pathways in this disease. This not only provides insights into the pathogenesis of diabetic cardiomyopathy but also assists in the identification of potential targets that may be useful for the therapeutic prevention and/or treatment of diabetic cardiomyopathy. Mechanisms of Mitochondrial Dysfunction in Diabetic Cardiomyopathy

The causes of diabetic cardiomyopathy are multifactorial and involve several closely related mechanisms that often feedforward, creating a vicious cycle of cardiomyocyte damage. However, the initiating event appears to be an early maladaptation in cardiac energy metabolism contributing to mitochondrial dysfunction and, eventually, impaired cardiac contractility. For the purpose of this review, we not only will focus mainly on the etiology of diabetic cardiomyopathy in T2D but also will briefly touch on T1D and some of the similarities and differences in their pathogenesis. Although the


initial cause of impaired glucose utilization is different between these two forms of diabetes, ultimately they share similar downstream metabolic consequences of a switch to greater cardiomyocyte FA utilization at the expense of glucose. Altered cardiac energy metabolism

The heart has one of the highest energy demands of any organ in the body and must continually produce ATP to sustain proper contractile function and ionic homeostasis (166, 187, 194). During normal physiological conditions, the healthy adult heart obtains > 95% of its ATP from mitochondrial oxidative phosphorylation (OXPHOS) (195). Therefore, changes in mitochondrial function and ATP production can have negative effects on contractility and it is clear that early derangements in cardiac energy metabolism contribute to the development of impaired cardiac function in diabetes (14, 26, 32, 229). Interestingly, the healthy heart relies on a balance between the oxidation of carbohydrates, FAs, and ketones as fuel sources, and it has the flexibility to switch substrates depending on physiological and pathological conditions (166). However, in the diabetic, the heart is characterized by reduced metabolic flexibility with a decrease in glucose utilization and an increased reliance on FAs via accelerated FAO (166). The shift in fuel preference away from glucose and toward increased FAO in the diabetic heart comes at a higher oxygen (O2) cost and reduces cardiac efficiency (ratio of cardiac work to MVO2) (25, 32, 75, 112, 175). In clinical studies using PET and 11C-palmitate, it has been shown that MVO2, FA uptake, and FAO are increased in obese young women (203) and in patients with T1D (108). Increased MVO2 and reduced cardiac efficiency is also the result of FA-induced mitochondrial uncoupling of ATP synthesis from MVO2, which may lead to generation of ROS, energy depletion, and cardiac dysfunction (25, 26). This increased use of FAs in the hearts of diabetics is dependent on several factors, including (i) FA supply and uptake into the cardiomyocyte, (ii) rate of TAG lipolysis, and (iii) mitochondrial function and FAO [refer to (166) for review]. All of these factors have been shown to be altered in the diabetic heart, leading to an overall chronic increase in FA utilization, which is known to impair cardiac function (11). FA supply and uptake into the cardiomyocyte. Hyperlipidemia, which is commonly observed in obesity and diabetes, arises when excessive lipolysis in expanded adipose tissue leads to elevated circulating plasma levels of FAs and TAG (121). Apart from this, accelerated synthesis of verylow-density lipoprotein TAG from the liver and chylomicrons from dietary absorption also contributes to high plasma FA levels (117, 159, 190). Although FFAs can cross the plasma membrane by passive diffusion, facilitated transport plays a major role in myocardial FA uptake (96). To date, three families/types of fatty acid transport proteins (FATPs) have been identified, including FATP, fatty acid binding protein (FABP), and CD36. Both CD36 (39, 57, 137, 169, 197, 249) and FABP (169) levels have been shown to increase in hearts from diabetic animals, suggesting that these proteins may also be involved in increasing FA uptake in the diabetic heart. Indeed, regardless of the mechanism of entry into the cardiomyocytes, elevated levels of cardiac FA uptake have been observed in rodent models of diabetes, including

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streptozotocin (STZ)-induced T1D (168), obese Zucker rats (56, 169), db/db mice (39), and rodents fed a high-fat diet (HFD) (96, 98, 197) [see (33) for review of animal models of diabetic cardiomyopathy], supporting the notion that excess FA uptake is a critical early step in the development of diabetic cardiomyopathy. While FATP, FABP, and CD36 have been shown to play a role in mediating FA transport into the cardiomyocytes (96), CD36 accounts for more than 50% of FA uptake in the heart (144, 185). Translocation of CD36 from intracellular stores to the sarcolemma is necessary for long chain FA uptake to occur (138, 170), and increased sarcolemmal content of CD36 is observed in the diabetic heart (56). Importantly, increased expression of CD36 has also been shown in cardiac myocytes from several T2D models (249), suggesting that CD36 may play an important role in increasing myocardial FA use in the diabetic. Consistent with this, inhibition of FA uptake via genetic ablation of CD36 protects the heart from age- and diet-induced myocardial FA accumulation and cardiac dysfunction (137, 249). In addition, deletion of CD36 rescued hearts in a mouse model of a cardiac-specific diabetic phenotype by reducing lipid accumulation, increasing glucose oxidation, and restoring cardiac function (283). Although preventing FA uptake via CD36 inhibition appears to improve myocardial metabolism by switching metabolism from FA to glucose, there are also other potential benefits discussed in the lipotoxicity section that may contribute to improved cardiac function in the diabetic. Rate of TAG lipolysis. Once inside the cell, FAs are rapidly esterified and converted into fatty acyl-CoA esters by a family of long chain acyl-CoA synthetases (ACSL) (76). Subsequently, FA have three major fates, including direct delivery to the mitochondria for oxidation, esterification to TAG for temporary storage in cytoplasmic lipid droplets, or delivery to the nucleus for the activation of gene transcription (132). Synthesis and hydrolysis of TAG stores are a tightly controlled and dynamic process that can regulate cardiac metabolism and function under basal conditions (133, 134). Therefore, it is not surprising that TAG hydrolases such as adipose triglyceride lipase (ATGL) play important roles in pathological conditions such as diabetic cardiomyopathy (31, 134). As ATGL is the rate-limiting TAG hydrolase in the heart (101, 102, 133), it was originally hypothesized that myocardial ATGL expression would be decreased in diabetes and that decreased ATGL activity would account for increased TAG levels (211). However, we have shown that increased cardiac expression of ATGL is associated with elevated TAG levels in mouse models of T1D (211) and HFD-induced T2D (210). Based on this, it was proposed that increased myocardial ATGL expression during diabetes was a compensatory but insufficient response to the increased FA availability (210, 211). Indeed, mice with a cardiac overexpression of ATGL (myosin heavy chain [MHC]-ATGL) were protected against intra-myocardial TAG accumulation, lipotoxicity, and cardiac dysfunction in STZ and HFD mouse models (210, 211). Since FAs liberated from the TAG pool can activate nuclear peroxisome proliferator-activated receptor-a (PPAR-a) signaling to further promote FA utilization (101, 102, 133, 134, 210, 211), TAG catabolism via ATGL strongly influences FA utilization in the heart by both supplying the heart with FAs for FAO and potentially activating PPAR-a/PGC1

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signaling and improving mitochondrial function (see section below). That said, the role that ATGL plays in the regulation of PPAR-a/PGC1 signaling in the heart has yet to be fully defined as different models appear to have some conflicting data (102, 133, 210, 211). Nevertheless, the regulation of TAG catabolism via ATGL may be a novel approach for a therapy aimed at manipulating cardiac energy metabolism. Thus, by targeting ATGL with the aim of mitigating FA supply to the heart, it may be possible to reduce FAO rates and the sequelae that eventually lead to cardiomyocyte and mitochondrial dysfunction—factors critical in the treatment of diabetic cardiomyopathy (Fig. 2). Mitochondrial function and FAO. The significant increase in cardiomyocyte FA utilization in the diabetic can not only

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be influenced by the degree of FA availability and increased FA transport but can also be attributed to increased FAmediated activation of PPAR-a (17, 75, 231). PPAR-a is an important nuclear transcription factor that increases expression of several genes encoding for proteins that promote FA utilization, including carnitine palmitoyal transferase (cpt)1, fatp1, cd36, and uncoupling proteins (UCPs) ucp2, and ucp3. In addition to facilitating FA uptake and oxidation, PPAR-a also increases expression of pyruvate dehydrogenase kinase 4, an inhibitor of pyruvate dehydrogenase (PDH), the key enzyme in glucose oxidation (74, 84, 94, 184). Of relevance, increased PPAR-a expression and activity has been reported in several rodent models of diabetic cardiomyopathy (84). The importance of PPAR-a activation in diabetic cardiomyopathy was demonstrated in mice with cardiac-specific overexpression of PPAR-a (MHC-PPAR-a). These MHCPPAR-a mice displayed dramatically elevated levels of cardiac FA uptake, storage, and oxidation with a concurrent reduction in glucose oxidation and glucose uptake that mimicked a diabetic phenotype. Most importantly, these metabolic changes are also associated with LVH and contractile dysfunction (84). In agreement with the overexpression of PPAR-a, mice that are deficient in PPAR-a have reduced expression of genes involved in FA utilization and reduced myocardial FAO rates (6, 153). Therefore, these two mouse models provide strong evidence that activation of PPAR-a plays an important role in mediating the observed derangements in myocardial energy metabolism and likely plays a key role in the development of cardiac dysfunction in diabetic cardiomyopathy. Excessive lipid accumulation

FIG. 2. Altered FA metabolism in diabetic cardiomyopathy. j FAs are taken up into the cell by passive diffusion across the plasma membrane or facilitated transport via FATPs, including CD36, FATP, and FABP. Once inside the cell, FAs can be k oxidized by the mitochondria to generate ATP, l esterified into the TAG pool to be stored temporarily, or m activate PPAR-a in the nucleus to promote transcription of genes involved in FA utilization, leading to increased FA uptake, FAO, and mitochondrial biogenesis. n Alternatively, FAs can also be liberated from the TAG pool by the hydrolase activity of ATGL that can be delivered to the mitochondria for oxidation or nucleus to activate PPAR-a. ATGL, adipose triglyceride lipase; ATP, adenosine triphosphate; FA, fatty acid; FABP, fatty acid binding protein; FAO, fatty acid oxidation; FATP, fatty acid transport protein; PPAR-a, peroxisome proliferator-activated receptor-a; TAG, triacylglycerol/triglycerides.

Although hearts from obese and diabetic animals are known to have accelerated rates of FAO, many of the animal models studied also have excessive intra-myocardial lipid accumulation (56). Therefore, it appears that, despite increased rates of FAO in the diabetic heart, FA uptake is well in excess of its capacity to be utilized. This imbalance between FA uptake and utilization results in the storage of FAs in the cardiomyocyte in the form of TAGs and/or conversion to other potentially detrimental lipid intermediates (31). Several studies have shown that excessive myocardial lipid accumulation, also known as cardiac steatosis, is deleterious to the heart, leading to numerous cardiac pathologies, including increased cardiomyocyte apoptosis, myocardial fibrosis, LVH, impaired diastolic filling, and contractile dysfunction (83, 84, 297). To establish whether or not perturbations in cardiomyocyte lipid uptake and metabolism directly contribute to cardiac dysfunction, several mouse models were generated with overexpression of FA-handling proteins (i.e., acyl-CoA synthetase 1, FATP1 and PPAR-a). All of these mouse models displayed a cardiac phenotype that was characterized by excessive lipid uptake, resulting in cardiac steatosis and impaired systolic function (50, 51, 133, 282). Interestingly, even in the absence of obesity or systemic metabolic disturbances such as hyperglycaemia, perturbed myocardial FA handling in these mice recapitulates the cardiac phenotype observed in diabetic cardiomyopathy. Overall, these findings suggest that excessive FA uptake and accumulation in the cardiomyocyte has detrimental effects on the heart, leading to diabetes-induced deterioration of function.


Elevated myocardial TAG levels have been associated with cardiac dysfunction in several genetic- and diet-induced models of diabetes (2, 31, 39, 91, 101, 133, 210). However, it is likely that lipotoxicity does not arise from an accumulation of TAG per se, but from the increased generation of potentially detrimental lipid intermediates, including ceramides, diacylglyercides (DAG), long chain acyl CoAs, and/or acylcarnitines (31). As such, there are several mechanisms by which excessive FA storage or cardiac steatosis can be potentially lipotoxic and lead to adverse effects on cardiac function (31). Moreover, ceramides and DAG have emerged as some of the more toxic lipid species that can lead to impaired insulin signaling (128) as well as to apoptotic cell death (109). Although ceramides are a key component making up cellular membranes, ceramides also act as a signaling molecule that can trigger apoptosis by inducing the release of cytochrome C from mitochondria (93). In addition, ceramide and DAG can lead to impaired cardiac insulin signaling by suppressing tyrosine phosphorylation of insulin receptors and insulin receptor substrates, thereby inhibiting activation of the PI3K/Akt pathway involved in insulin signaling (128). Increased intra-myocardial ceramide and DAG levels have been observed in numerous rodent models of diabetic cardiomyopathy and are associated with cardiac dysfunction (84, 267, 292, 297). Moreover, pharmacological and genetic inhibition of ceramide synthesis reduced cardiac ceramide levels and palmitate oxidation rates, as well as restored glucose oxidation rates and cardiac function in mouse models of lipotoxicity (199, 267). Similarly, mice with cardiac-specific overexpression of hormone-sensitive lipase, an important lipase catalyzing the hydrolysis of DAG, protected hearts from STZ-induced cardiac lipid accumulation and mortality (265). Although cardiac FAO is known to be accelerated in diabetes, some studies in genetically engineered mice have suggested that a further increase of FAO may aid in reducing the degree of cardiac lipid accumulation and in improving

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cardiac function (162, 241). As a whole, these data in animal models support the idea that accumulation of ceramides, DAG, or acylcarnitines is potentially lipotoxic, resulting in the worsening of insulin resistance and cardiac dysfunction in diabetes. Alternatively, Koves et al. (142) have shown that improving complete FAO in the mitochondria may reduce skeletal muscle insulin resistance. Therefore, potentially a similar approach to increase complete FAO in the heart may also be beneficial to improve insulin resistance. As such, therapies aimed at reducing the accumulation of ceramides and DAG by inhibiting their production or reducing FA uptake into the cardiomyocyte could prove to be protective in diabetic cardiomyopathy (Table 1). Impaired cardiac insulin signaling and glucose metabolism

It is known that the heart also becomes insulin resistant in T2D, and this cardiac insulin resistance is associated with cardiac contractile dysfunction (32). However, in contrast to the considerable amount of work involved in investigating the effects of excess myocardial lipids in diabetes, less is known about the mechanisms that mediate insulin resistanceinduced cardiac dysfunction. As such, it is still not completely clear whether/how impaired cardiac insulin signaling and/or glucose utilization contribute to the development of cardiac dysfunction in the diabetic heart (34). In addition, since animal models of T2D and diet-induced models also commonly display hyperglycemia, hyperlipidemia, obesity, and fluctuations in hormones, it is difficult to tease out the direct effects of impaired cardiac insulin signaling. However, a mouse model with a cardiomyocyte-specific deletion of the insulin receptor (CIRKO mice) has been generated that has allowed testing of whether impaired insulin signaling in the absence of systemic alterations in metabolism influences cardiac function (24). Studies using the CIRKO mice have shown that these mice have reduced insulin-stimulated glucose uptake and gradually

Table 1. Mitochondrial Dysfunction and Altered Metabolism in Animal Models of Type 1 and Type 2 Diabetes and Selected Transgenic Models of Diabetes Cardiac function Type 1 diabetes Streptozotocin Y (85, 211) Ins2 + / - Akita Y (35) OVE26 Y (234, 284) Type 2 diabetes db/db Y (26, 32, 70) ob/ob [/Y (32, 175) UCP-DTA ZDF Y (97, 297) Genetically modified mice MHC-PPARa Y (84) CIRKO Y (13, 24) icATGL KO Y (133) FATP1 Y (50) ACSL1 Y (51) hLpLGPI Y (282)

Mitochondrial function Y (85, 149) Y (35, 36) Y (234) Y (26) Y (25) Y (75)

Y (24)

Cardiac efficiency Y (112) — (35) Y (26, 32) Y (32, 175)

— (24)

Fatty acid oxidation

Glucose oxidation

Lipid accumulation

[ (112) [ (35)

Y (112) Y (35) Y (284)

[ (211) [ (211)

[ (14, 26, 32) [ (32, 175)

Y (26, 32) Y (32, 175)

[ (103) [ (32)

[ (275)

Y (42, 97)

[ (297)

Y (84) Y (13)

[ (84)

[ Y Y [

(84) (13) (133) (50)

[ [ [ [

(133) (50) (51) (282)

ACSL1, acyl-CoA synthetase 1; hLpLGPI, glycosylphosphatidylinositol anchored human lipoprotein lipase; icATGL KO, inducible cardiomyocyte-specific ATGL knockout; MHC, myosin heavy chain; UCP-DTA, uncoupling protein-diphtheria toxin A; ZDF, Zucker diabetic fatty rat; [, increase; Y, decrease; —, no change.

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develop a decrease in glucose and FAO, as well as modest cardiac dysfunction with age (13, 24). Furthermore, hearts from CIRKO mice have impaired mitochondrial respiration and ATP synthesis rates, as well as reduced gene expression of OXPHOS mitochondrial proteins, FA handling proteins, and tricarboxylic acid (TCA) cycle proteins (24). CIRKO mice also exhibit increased mitochondrial ROS generation and mitochondrial uncoupling (24), suggesting that impaired cardiac insulin signaling is linked to mitochondrial dysfunction and oxidative stress (Table 1). Conversely, overexpression of human GLUT4 glucose transporter in hearts of db/db mice normalized cardiac glucose and FA metabolism and restored cardiac function in these hearts (229), suggesting that promoting glucose oxidation, in this case by increasing glucose uptake via GLUT4, can restore normal cardiac function. Therefore, targeting the alterations in cardiac energy metabolism specifically by improving insulin sensitivity and promoting glucose metabolism may be effective in preventing the development of diabetic cardiomyopathy. Since cardiac insulin resistance is one of the earliest cardiac manifestations of T2D, impaired cardiac insulin signaling may be an important mechanism in the progression of diabetic cardiomyopathy. Contrary to this, some studies have shown that the hyperinsulinemia present in T2D leads to persistent activation of the insulin receptor that occurs in the absence of increased basal downstream Akt activation (55, 175). Since it has been shown in healthy mice that insulin may directly impair badrenoreceptor-regulated cardiac contractility (87), it has been suggested that this may provide a potential explanation of reduced myocardial inotropic reserve in pathological states of hyperinsulinemia such as T2D. Therefore, further investigation into the role of insulin signaling and adrenergic response in the development of diabetic cardiomyopathy is needed. Data from experimental animal studies suggest that common anti-diabetic treatments targeted at improving systemic insulin resistance and glycemic control such as metformin (53, 77, 285) and troglitazone (214) are also able to prevent moderate cardiac dysfunction in the early stages of T2D. Indeed, some clinical studies, including the UK Prospective Diabetes Study and Hyperinsulinemia: the Outcome of its Metabolic Effects trials, have shown that metformin reduces cardiovascular risk for patients with T2D (1, 139). However, the recent double-blinded, placebo-controlled trial Carotid Atherosclerosis: MEtformin for insulin ResistAnce showed little cardiovascular benefit in non-diabetic patients with coronary heart disease using carotid intima-media thickness as a primary endpoint (209). Apart from this, the Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction Trial (GIPS-III; NCT01217307) showed that metformin did not improve LVEF in non-diabetic patients with ST-segment elevation myocardial infarction who underwent percutaneous coronary intervention (154). These findings have called into question whether metformin indeed has cardiovascular benefit. Further evidence from large trials of cardiovascular outcomes such as the Metformin in CABG trial (MetCAB; NCT01438723) will shed more light on this question. Altered cytosolic and mitochondrial calcium handling

Cardiomyocyte contraction is highly dependent on the concentrations of intracellular Ca2 + and ATP. It is becoming

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increasingly evident that alterations in cardiomyocyte Ca2 + handling may be critical in the regulation of cardiac function in diabetic cardiomyopathy (15, 70, 82, 143, 165, 188, 200, 296). Usually, Ca2 + influx into the cell via the L-type Ca2 + channel triggers sarcoplasmic reticulum (SR) Ca2 + release, which raises cytosolic free [Ca2 + ]. This leads to binding of Ca2 + to troponin C (TnC), causing a conformational change and allowing the interaction of actin and myosin to produce contraction. For ventricular relaxation and diastolic filling to occur, cytosolic [Ca2 + ] must decline allowing the dissociation of Ca2 + from TnC. Ca2 + removal from the cytosol is mediated primarily by the actions of the ATP-dependent sarcoplasmic reticulum Ca2 + -ATPase 2a (SERCA2a), which transports Ca2 + back into the SR. Indeed, depressed cardiac function is known to be associated with impaired SRmediated Ca2 + handling in both T1D (143, 165, 188, 200, 296) and T2D (15, 70, 82). Reduced SERCA2a pump activity is the result of decreased expression and/or Ca2 + affinity of SERCA2a or increased expression of its inhibitory protein phospholamban (15, 70, 82, 143, 165, 188, 200, 296). Although the precise mechanism responsible for reduced SERCA2a activity is not known, it has been proposed that oxidative stress results in increased formation of advanced glycation endproducts and O-linked b-N-acetylglucosamine modifications of the SR membrane and proteins, leading to depressed SERCA2a expression and/or function (20, 156). The functional significance of impaired Ca2 + handling is shown in mice with a cardiomyocyte-specific deletion of SERCA2a that develop LV dysfunction (22), whereas overexpression of SERCA2a improves systolic and diastolic function in STZ-induced T1D mice presumably by improving SR Ca2 + sequestration (246, 262). Therefore, perturbations in myocyte Ca2 + handling may lead to cardiac dysfunction and likely contribute to the development of diabetic cardiomyopathy, making it a current therapeutic target of interest. In addition, impaired sympathetic nervous system activity has been observed in T1 and T2 diabetic hearts and has been linked to the progression of diabetic cardiomyopathy (68). Earlier, this was characterized by hyperactivity and elevated norepinephrine (NE) spillover that can progress to sympathetic denervation and reduced NE release, a condition known as cardiac autonomic neuropathy (258). Sympathetic hyperactivation coupled with hyperglycemia in T2D may lead to a rise in ROS levels and impaired mitochondrial respiration, which can exacerbate impaired Ca2 + handling and excitation-contraction coupling, leading to contractile dysfunction in the diabetic heart (261). New research has focused on the role of mitochondrial Ca2 + handling in diabetic cardiomyopathy. Although the primary function of the mitochondria is ATP generation, it can also store Ca2 + , which allows mitochondria to act as a Ca2 + buffer to prevent cytosolic Ca2 + overload (64). Ca2 + is rapidly transported down the electrochemical gradient into the mitochondrial matrix via a Ca2 + uniporter protein complex and extruded via the Na + /Ca2 + exchanger on a beat-tobeat basis in the heart, contributing to fast buffering during the excitation–contraction coupling (73, 171, 250). Consequently, increased cytosolic Na + levels found in myocytes from diabetic animals may also impair mitochondrial Ca2 + uptake (171). Since Ca2 + regulates several important cellular processes, such as muscle contraction, the close proximity of


mitochondria to SR Ca2 + release sites suggests that Ca2 + shuttling between the cytosol and the mitochondria may represent a signaling network coordinating the rate of ATP production with its demand for cardiac contraction (34, 72, 82, 95, 118). There are several mitochondrial enzymes that are Ca2 + sensitive, including TCA cycle enzymes isocitrate dehydrogenase and a-ketoglutarate dehydrogenase and PDH (95). Studies in isolated cardiac mitochondria show that elevations in mitochondrial Ca2 + result in activation of these Ca2 + sensitive dehydrogenases, as well as in increases in ATP production and TCA cycle activity (72, 104, 125, 217). To date, few studies have investigated mitochondrial Ca2 + handling defects in diabetic models (82, 85, 205, 255). However, Flarsheim et al. (85) showed that as early as 2 weeks after STZ treatment in rats (before the development of systolic cardiac dysfunction) there was a significant reduction in the rate of Ca2 + uptake into isolated cardiac mitochondria. This was associated with a reduced capacity to upregulate ATP synthesis via stimulation of PDH and a-ketoglutarate dehydrogenase (85). Therefore, reduced mitochondrial Ca2 + uptake may compromise ATP synthesis rates required for proper cardiac contraction and likely contribute to eventual cytosolic Ca2 + overload, thereby contributing to the development of diabetic cardiomyopathy (Fig. 3).

FIG. 3. Impaired cellular and mitochondrial Ca21 handling in diabetic cardiomyopathy. Cytosolic Ca2 + concentrations increase due to influx of Ca2 + into the cardiomyocyte via L-type Ca2 + channels, which trigger release of stored Ca2 + from the SR. Increased cytosolic Ca2 + is necessary for actin–myosin interaction and cardiac contraction, and removal of intracellular Ca2 + is required for relaxation and ventricular filling, in part, via re-uptake of Ca2 + into the SR via the SERCA2a. In diabetes, a reduction in SERCA2a activity and expression results in reduced Ca2 + uptake into the SR and, eventually, leads to cytosolic Ca2 + overload and impaired cardiac contractile function. Furthermore, mitochondrial Ca2 + uptake is impaired in diabetes, which decreases activation of Ca2 + sensitive hydrogenases PDH and TCA cycle enzymes. Ultimately, this reduces mitochondrial ATP production and contributes to reduced myocardial contractility. Ca2 + , calcium; PDH, pyruvate dehydrogenase; SERCA, sarcoplasmic reticulum Ca2 + -ATPase; SR, sarcoplasmic reticulum; TCA, tricarboxylic acid.

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Oxidative stress

ROS are essential for normal function and activity of cell signaling molecules (43). However, ROS production is under tight physiological control to prevent oxidative damage. Oxidative stress results from an imbalance between the generation of ROS and endogenous antioxidant capacity (280). Depending on the accumulated level of ROS, these highly reactive molecules can induce many pathophysiological effects on the cell, including direct oxidation of DNA, proteins, and lipid (280), as well as activation of stresssensitive pathways leading to cell damage (80). ROS production in cardiomyocytes can also trigger and advance the cardiac remodeling process as shown by blunted cardiomyocyte hypertrophy in response to antioxidant treatment (186). Oxidative stress is also a key regulator of myocardial fibrosis (295), which is a feature of cardiac remodeling in diabetic cardiomyopathy. Many studies show increased ROS generation in models of diabetic cardiomyopathy as well as reduced endogenous antioxidant defenses in diabetes (3, 173). Indeed, Tocchetti et al. (261) demonstrated that deficient mitochondrial glutathione and thioredoxin antioxidant systems in the T2D db/db mouse account for excess mitochondrial ROS production. They also showed that this deficiency in mitochondrial antioxidant capacity was a causative factor in impaired excitationcontraction coupling in isolated cardiomyocytes or whole heart preparations (261). As expected, oxidative stress in diabetic cardiomyopathy correlates with excess lipid delivery and elevated mitochondrial FAO rates (269), factors that are characteristic in the setting of obesity and diabetes (73). Although the direct impact of lipid oxidation in mitochondria is unclear, it has been observed that lipids can inhibit or uncouple OXPHOS (279). Hyperglycemia itself induces an overproduction of ROS and is believed to be a causal link between increased circulating glucose and the onset and progression of diabetic complications such as diabetic cardiomyopathy (218). In fact, a hyperglycemia-induced increase in electron transfer donors (such as NADH and FADH2) results in increases in electron flow through the mitochondrial ETC. Subsequently, the ATP/ ADP ratio increases and mitochondrial membrane potential is hyperpolarized. Downstream effects of this include an accumulation of electrons to coenzyme Q, driving the generation of the free radical superoxide. Thus, it has been proposed that these hyperglycemia-induced events result in the generation of ROS that is, in turn, believed to be the fundamental driver of mitochondrial dysfunction that figures so prominently in diabetes-related complications such as diabetic cardiomyopathy (218). Lastly, in the heart, the predominant sources of ROS are from NADPH oxidases, uncoupled nitric oxide synthases (NOS), and, importantly, the mitochondrial respiratory chain itself, which is the main intracellular source of free radicals in the diabetic heart. In addition, recent evidence suggests that monoamine oxidase A and B are contributors to the excessive ROS production characteristic of cardiac dysfunction (126, 127). Indeed, monoamine oxidases as well as the sources of ROS mentioned earlier are upregulated in diabetes and believed to directly contribute to the pathogenesis of diabetic cardiomyopathy (115, 116, 145, 189). NADPH oxidase is a major source of ROS in cardiovascular cells, including cardiomyocytes (228), and is usually

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activated to generate superoxide to destroy pathogens. It comprises several Nox isoforms, with the primary cardiac isoforms being Nox 2 and Nox 4 (281). NADPH oxidase activity and expression is upregulated in the setting of LVH and HF (160, 293) and is also increased in diabetes in conjunction with myocardial hypertrophy and fibrosis (115, 230). Another source of ROS, in addition to NADPH oxidase, is uncoupled endothelial nitric oxide synthase (eNOS), which can generate superoxide in the cardiovascular system. Usually, eNOS generates NO in the vasculature via tightly controlled electron transfer (135). However, if there is uncoupling between O2 reduction and NO generation, superoxide is produced. This eNOS uncoupling is present in diabetes and contributes to oxidative stress in this condition (81). Another major source of myocardial ROS is the mitochondrial respiratory chain (71). Mitochondria, as the site of OXPHOS, usually generate superoxide under physiological conditions over the course of the energy-generating pathway (27). This normal ROS generation is quenched by endogenous anti-oxidant mechanisms. However, if the inner mitochondrial membrane potential rises beyond a certain level, extra ROS generation is triggered (140). Such a rise in membrane potential can be a result of increased glucose or FAO (239), the latter of which is certainly increased in diabetic cardiomyopathy. Cardiac ROS accumulation can subsequently cause contractile dysfunction via damage of intracellular organelles and proteins. This generation of ROS is critical in physiological signaling. However, under normal conditions, ROS is quenched by endogenous anti-oxidant mechanisms, thus maintaining a delicate balance between ROS production for normal cellular function and scavenging to prevent damage to cellular components and tissues. The link between mitochondrial respiration and ROS generation is unclear and a topic of some debate in the literature given the recognized role of oxidative stress-induced mitochondrial dysfunction in diseases such as diabetic cardiomyopathy. One theory suggests that once the inner mitochondrial membrane potential rises beyond a certain level, extra ROS generation is triggered (140). Such a rise in membrane potential can be a result of increased FAO (239), which is certainly increased in diabetic cardiomyopathy. Conversely, emerging evidence suggests that a loss of mitochondrial membrane potential may compromise the ROS-scavenging capacity of this organelle, thus contributing to increased ROS accumulation (5). Indeed, mononuclear cells and platelets from T2D patients exhibit reduced mitochondrial membrane potential (100, 277), which is believed to contribute to the vascular dysfunction characteristic of this disease. This recently introduced, novel perspective is termed the Redox-Optimized ROS Balance hypothesis. This hypothesis shifts the focus away from mitochondrial membrane potential as the driving force for ROS generation and instead is centered on the cellular redox environment. In an optimal (physiologically stable) redox environment, ROS production is minimal and supportive of normal cellular signaling processes. By contrast, in either highly reduced or highly oxidized redox environments, ROS accumulation or overproduction can result. Based on this proposal, mitochondrial ROS generation is modulated by the balance between ROS production and scavenging and this balance is disrupted at reduced or oxidized extremes. Thus, in a reduced cellular environment, slow electron flow through the respi-

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ratory chain predisposes the production of superoxide, whereas in an oxidized cellular environment, ROS-scavenging capacity is impaired, resulting in ROS accumulation (5, 58). Although this is an interesting hypothesis that merits further investigation, based on the existing evidence it is difficult to draw a definitive conclusion regarding the mechanism of mitochondrial ROS production in diabetic cardiomyopathy at this time. In addition to increased ROS production, dysfunctional ROS scavenging in the diabetic heart contributes to the severity of oxidative stress. In fact, overexpression of the endogenous antioxidant catalase can restore cardiomyocyte contractility in T1D mice (284). The increase in cardiac oxidative stress also occurs due to cytosolic ROS-induced exacerbation of mitochondrial ROS production (90). This is a key feature in diabetic cardiomyopathy, in which oxidative damage to mitochondria leads to further mitochondrial dysfunction (298, 299). Although the mitochondria are themselves equipped with powerful antioxidant defenses to protect against ROS generation, when this mechanism is compromised, the mitochondrial structures suffer oxidative damage, and mitochondrial DNA are particularly sensitive (274). In diabetic cardiomyopathy, mitochondrial oxidative damage sets in motion a vicious cycle whereupon mitochondrial oxidative damage exacerbates ROS production from these organelles, leading to increased cardiac ROS accumulation and further mitochondrial oxidative damage. Anderson et al. (4) not only demonstrated mitochondrial dysfunction in atrial tissue of diabetic patients, including those with tight glycemic control, but also showed increased mitochondrial peroxide release and depletion of mitochondrial antioxidant molecules (4). The importance of oxidative stress in the pathogenesis of diabetic cardiomyopathy is also highlighted by studies in which endogenous antioxidants (superoxide dismutase, catalase, and glutathione peroxidase) have been overexpressed. These studies demonstrate a significant improvement in contractile function in diabetic rodents (174, 234, 284) and highlight the importance of investigating the consequences of ROS in the diabetic heart and strategies to reduce this oxidative stress as discussed later in this review (Fig. 4). Although ROS can contribute to mitochondrial oxidative damage in hearts from diabetics, ROS can also further compromise mitochondrial function via induction of the mitochondrial permeability transition (106, 113, 114). This phenomenon involves opening of the mitochondrial permeability pore in the inner membrane of mitochondria, which leads to further mitochondrial injury and cell death. Mitochondria utilize electron transport to generate an electrochemical gradient across the inner membrane, which is used by ATP synthase to generate ATP. The inner membrane must be virtually impermeable to ions to sustain this membrane potential and, thus, ATP-generating capacity of the mitochondria. Given the sensitivity of the membrane permeability pore to ROS, the opening of this complex can occur in the setting of diabetes and results in depolarization of the inner membrane potential, causing ATP synthase to operate in reverse and shifts mitochondria from ATP producers to ATP consumers (238). This rapidly depletes cellular energy levels and leads to susceptibility to injury and, eventually, cell death. ROS also sensitize the mitochondrial permeability transition pore to Ca2 + induced opening (8), leading to Ca2 + overload and further


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FIG. 4. Pathophysiological mechanisms contributing to mitochondrial dysfunction in diabetes. The characteristic increase in FFAs drives increased cellular FA uptake (via FA transporters such as FATP and CD36) mediated by increased PPAR-a and PGC-1a activity. Increased FA uptake fuels an increase in FAO, precipitating increased ROS production and mitochondrial oxidative damage. The ensuing mitochondrial dysfunction triggers increased mitochondrial ROS production and in conjunction with reduced mitochondrial anti-oxidative capacity and increased cellular ROS, drives a vicious cycle resulting in further mitochondrial oxidative damage. Increased FFA stimulates increased UCP activity, which results in mitochondrial uncoupling, reduced ATP production, and compromised cardiac function. Additional mechanisms contributing to mitochondrial dysfunction include a diabetes-induced increase in mitochondrial biogenesis and altered mitochondrial Ca2 + handling and membrane phospholipid content. AGEs, advanced glycation endproducts; FFA, free fatty acid; O-GlcNAc, O-linked b-N-acetylglucosamine; PGC-1a, peroxisome proliferator-activated receptor c co-activator 1a; ROS, reactive oxygen species; UCP, uncoupling protein. exacerbating the membrane permeability transition (192). In line with this, heart mitochondria from T2D rats accumulate Ca2 + more rapidly than controls (191). Overall, mitochondria from diabetic human and animal hearts are more susceptible to opening of the membrane permeability transition pore (18, 193, 278). This appears to be the case for both types of diabetes, since T1D rat hearts demonstrated a greater propensity for ischemic injury that was attributed to ROS-dependent induction of the mitochondrial permeability transition (240). Thus, not only can ROS lead to contractile dysfunction, but also the high circulating ROS characteristic of diabetes can further impair mitochondrial function by sensitizing the mitochondrial membrane permeability transition pore to opening in response to ROS or circulating Ca2 + , leading to Ca2 + overload, loss of ATP-generating capacity, mitochondrial rupture, and, ultimately, cardiomyocyte death (Fig. 4). Consistent with the importance of the mitochondrial permeability transition pore in diabetes, inhibition of the mitochondrial permeability transition is shown to be cardioprotective in humans (206). Mitochondrial uncoupling

As introduced earlier, a potential mechanism underlying the mismatch between increased MVO2 and reduction in cardiac energy generation and efficiency in diabetes may involve mitochondrial uncoupling and UCPs. In non-cardiac tissues such as brown adipose, UCPs are important for generating heat by uncoupling O2 consumption from ATP production (236). Although the precise role of UCPs in the heart is not fully understood, UCP homologues 2 and 3 are expressed in the myocardium (150) and mitochondrial un-

coupling has been described in diabetic rodent hearts (23, 25, 26). In the mitochondria, UCPs are believed to play a physiological role in the setting of increased mitochondrial substrate flux to decrease the proton gradient and thus limit ROS production (27, 28). Mitochondrial UCPs channel protons from the intermembrane space into the matrix space to bypass F0F1-ATPase, thus reducing ATP production. However, the rise in ROS in diabetes may persistently activate mitochondrial UCPs, resulting in inappropriate dissipation of the proton gradient, chronically reducing ATP production, which ultimately compromises cardiac function. This is the essential basis of the general mechanism leading to mitochondrial uncoupling in diabetic cardiomyopathy and is supported by data demonstrating a restoration of mitochondrial proton gradient to normal levels after inhibition of UCPs (26). However, it must be noted that mitochondrial uncoupling may be a feature unique to T2D, since experimental models of T1D do not show impaired cardiac efficiency or mitochondrial uncoupling although cardiac FAO is increased (35). Although it is currently unclear why this is the case, a new hypothesis describing modulation of mitochondrial ROS production has been proposed and is termed RedoxOptimized ROS Balance (see above for discussion) (5, 58). Another potential differentiating factor may be insulin resistance. Supporting this idea are data demonstrating the development of FA-induced mitochondrial uncoupling in the setting of euglycemia in mice featuring cardiomyocytespecific deletion of insulin receptors (24). Thus, increased UCP expression in hearts from diabetics may have a role in mitochondrial uncoupling that is observed in diabetic cardiomyopathy and, ultimately, contribute to the reduction in

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cardiac energy production and efficiency despite increased FAO rates (Fig. 4). In addition to UCPs, apolipoprotein O (APOO) was recently discovered to be localized to the inner mitochondrial membrane and also causes mitochondrial uncoupling, increased O2 consumption, and ROS production (263). Of importance, APOO was found to be highly expressed in hearts from diabetic patients (147) and in rodent hearts after 9 weeks of HFD (204). Cardiac overexpression of APOO in mice fed an HFD led to mitochondrial structural abnormalities and modestly impaired systolic function (263). Together, these data suggest that APOO-induced proton leak and increased respiration may eventually lead to depletion of NADH and FADH substrates, which the cardiomyocyte may attempt to compensate for by increasing FA uptake. However, this increased FA uptake may eventually be lipotoxic, contributing to oxidative mitochondrial damage as discussed earlier and facilitating the development of cardiac dysfunction in diabetes. Mitochondrial biogenesis

Mitochondrial biogenesis is an intricate and continuous process that controls the number and composition of mitochondria in all tissues (232). Mechanisms that stimulate increased mitochondrial biogenesis also trigger increased mitochondrial DNA replication and assembly of proteins into mitochondrial matrix and membranes (111). Although diabetes increases the initiation and progression of mitochondrial biogenesis (123), the specific targets of diabetes in this process have not been clearly defined. It is known that the transcriptional co-activator peroxisome proliferatoractivated receptor c co-activator 1a (PGC-1a) is a major regulator of mitochondrial biogenesis (131). Indeed, cardiomyocyte-specific overexpression of PGC-1a not only results in a significant increase in cardiomyocyte mitochondrial number but also causes contractile dysfunction (222). Conversely, cardiac-specific knockout of PGC-1a reduces expression of genes related to FAO, TCA cycle, and OXPHOS without altering the density of the mitochondria (7). Since increased mitochondrial biogenesis is characteristic of diabetes (172), it is possible that activation of PGC-1a could be involved in regulating this process. However, this has not been established definitively. Paradoxically, although mitochondrial content is increased in the hearts of insulin resistant and diabetic animals, mitochondrial respiration and ATP synthesis is actually reduced (75). As such, stimulation of mitochondrial biogenesis is a potentially adaptive mechanism in the face of compromised mitochondrial function and cardiac energetics in diabetic cardiomyopathy. However, this adaptation is not matched with an equal compensation of mitochondrial respiration, so it is currently not known whether this is a beneficial/adaptive or detrimental/maladaptive mechanism (Fig. 4). Metabolic Treatments for Diabetic Cardiomyopathy

Since the diabetic heart exhibits major metabolic changes such as increased FAO, reduced glucose oxidation, and impaired insulin sensitivity and these appear to be detrimental to cardiac function, therapies aimed at inhibiting myocardial FA metabolism and reciprocally promoting glucose metabolism may be a promising approach to the treatment of diabetic

FIG. 5. Targets of metabolic inhibitors in the treatment of diabetic cardiomyopathy. FA uptake into the cardiomyocyte can be inhibited via specific CD36 inhibitor AP5055 and AP5258. The CPT1 inhibitors etomoxir, perhexiline, and MCD inhibitors can inhibit FA uptake into the mitochondria for FAO and ATP production. The partial inhibitors of FAO, including trimetazidine and ranolazine, inhibit FAO via inhibition of specific FAO enzymes. These agents shift myocardial energy metabolism in diabetes from FAO to glucose oxidation and, ultimately, reduce cardiac dysfunction associated with diabetic cardiomyopathy. CM, chylomicrons; CPT1, carnitine palmitoyal transferase 1; LPL, lipoprotein lipase; MCD, malonyl-CoA decarboxylase; TG, triacylglyceride; VLDL, very low density lipoprotein.

cardiomyopathy. Existing approaches include inhibition of cellular and mitochondrial FA uptake and partial inhibition of FAO (Fig. 5). Inhibitors of cellular and mitochondrial FA uptake

Since CD36 appears to play a central role in mediating excessive myocardial FA uptake in hearts from diabetic animals (249, 283), small-molecule inhibitors of CD36 that block FA binding to CD36, and thus reduce uptake, have recently been developed (92). Administration of the CD36 inhibitors AP5055 or AP5258 for 3 weeks to the Zucker diabetic fatty rat diabetic rat reduced fasting and dietary plasma glucose levels by 20%–50% (92). CD36 is also well known for its role in the uptake of oxidized low-density lipoprotein into macrophages, and AP5055 also protected against the development of atherosclerosis via formation of smaller plaques with less lipid deposition (92). These CD36 inhibitors are not only yet to be tested in regards to their potential effects in diabetic cardiomyopathy but may also prove to be effective to prevent


excessive FA accumulation in the heart, which could, subsequently, improve function. Several studies have shown that direct inhibition of mitochondrial FA uptake is an effective approach to shift myocardial energy metabolism from FA to glucose utilization (120). CPT1 is an important rate-limiting step that is responsible for long chain FA uptake into the mitochondria for subsequent oxidation and is under the transcriptional control of PPAR-a (176). Inhibitors of CPT1 such as etomoxir and perhexiline, which inhibit mitochondrial FA uptake, have been studied for this purpose. Etomoxir is an irreversible CPT1 inhibitor that has been shown to inhibit FAO and cause reciprocal activation of glucose oxidation via actions on PDH (164, 167). When administered to diabetic rats, etomoxir was shown to increase glucose oxidation rates (273) and ameliorate cardiac dysfunction (107, 226). Interestingly, chronic treatment of rats with etomoxir also induces the expression of SERCA2a in the heart (271) and increases rates of SRmediated Ca2 + uptake (220, 221, 271), which may improve Ca2 + handling, ATP production, and cardiac function in the setting of diabetes. Consistent with animal studies, both etomoxir and perhexiline improve LV ejection fraction in patients with HF (152, 225). However, some caution is warranted with the use of etomoxir, as the Etomoxir for the Recovery of Glucose Oxidation randomized placebocontrolled study had to be stopped early due to several patients in the moderate HF group developing abnormal liver function (110). Although etomoxir and perhexiline have not been tested specifically for the treatment of diabetic cardiomyopathy in patients, both drugs improve cardiac function in patients with HF, a pathology that is also characterized by compromised metabolism and cardiac energy deficiency. Therefore, direct FA inhibitors hold promise to also be useful in patients with diabetic cardiomyopathy. In addition to drugs that directly inhibit CPT1, drugs that elevate malonyl CoA levels have also been designed to inhibit CPT1. One example of this is malonyl-CoA decarboxylase (MCD) inhibitors (45–47, 78). MCD catalyzes the degradation of malonyl-CoA to acetyl-CoA and removes inhibition of CPT1 by malonyl-CoA. MCD expression is highly regulated by PPAR-a transcriptional control (37, 61, 151), and studies have shown that cardiac MCD activity and expression are increased in HFD and STZ-induced diabetes likely via increased PPAR-a activation (37). The use of MCD inhibitors in animal models results in reduced FAO, increased glucose oxidation, and improved insulin sensitivity (244). In addition, mice with MCD deficiency are protected against the development of impaired insulin-stimulated glucose metabolism in response to a HFD (268). Therefore, inhibition of mitochondrial FA uptake via MCD inhibition may represent a novel mechanism for altering the balance of cardiac energy metabolism in diabetic cardiomyopathy. However, it remains to be shown whether MCD inhibitors can result in improved cardiac function in animal models of diabetes and in humans. Partial inhibitors of FAO

Trimetazidine is a partial FAO inhibitor that competitively inhibits mitochondrial long chain 3-ketoacyl-CoA thiolase, the last enzyme in the FA b-oxidation pathway. By inhibiting FAO, trimetazidine shifts substrate preference to glucose

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oxidation (130, 163). Currently, trimetazidine is approved as an anti-anginal agent throughout Europe and Asia. Animal studies show that trimetazidine improves recovery after myocardial ischemia-reperfusion injury by reducing proton production and disturbances in ionic homeostasis arising from the uncoupling of glycolysis to glucose oxidation (130, 163). Apart from this, trimetazidine may exert favorable effects on oxidative stress and cardiomyocyte Ca2 + handling by improving SERCA2a activity and preventing intracellular Ca2 + overload (179), which are also important pathological mechanisms known to lead to diabetic cardiomyopathy. Recently, trimetazidine administered to db/db mice (157) and diet-induced obese mice (266) was found to significantly improve cardiac function and protect the heart against lipid accumulation and oxidative stress. Clinically, 6 months of trimetazidine treatment improved cardiac function and physical activity tolerance level in diabetic patients with idiopathic dilated cardiomyopathy (294). Similarly, ranolazine, which is also believed to act by suppressing FAO (227), has been shown to lower fasting glucose and HbA1c (49, 183, 260). Although less is known about the mechanism of action and effectiveness of ranolazine, it has been shown to reduce angina events in patients (141). Therefore, trimetazidine and ranolazine, which have already been clinically approved for the treatment of chronic stable angina, may also have beneficial effects in diabetic cardiomyopathy and could be combined with concurrent anti-diabetic medications, especially since they have the added benefit of improving glycemic control. Alternative treatments for diabetic cardiomyopathy— spotlight on resveratrol

The heart requires optimal mitochondrial function and ATP production to meet the high-energy demands of normal cardiac performance. In diabetes, mitochondrial function is compromised by the multiple mechanisms reviewed earlier, which leads to contractile dysfunction and, ultimately, diabetic cardiomyopathy. From the previous discussion, it is apparent that strategies that improve energy metabolism and substrate preference may have therapeutic benefit in preventing diabetic cardiomyopathy or improving myocardial function in diabetes. One approach that may provide additional benefits may be supplementation of existing treatment strategies with the natural compound resveratrol. Resveratrol (3,5,4¢-trihydroxy-trans-stilbene) is a polyphenol that is produced by plants and is present in a variety of plant-based foods. Many beneficial properties of resveratrol have been demonstrated, including cardioprotection (233), anti-cancer effects (155, 287), and lifespan extension (79, 196). Resveratrol also appears to show promising results in diabetes management (105) and may be worthy of consideration as an adjuvant to traditional diabetes treatment strategies. Although specific data regarding the impact of resveratrol treatment on diabetic cardiomyopathy are quite limited at this time, it is clear that resveratrol has systemic anti-diabetic effects in models of both T1D and T2D (207). Management of T1D and T2D involves blood glucose control, while management of T2D additionally involves preservation of pancreatic b-cells and improved insulin sensitivity. Resveratrol has been shown to improve these three facets of diabetes control (207). Thus, by reducing hyperglycemia, increasing

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tissue glucose uptake and preserving endogenous insulin secretory capacity (21, 44, 48, 198, 207, 237, 245, 251–254), resveratrol is able to control the systemic factors that contribute to the development of diabetic cardiomyopathy— without the negative side effects reported for traditionally used anti-diabetic agents such as metformin (59). In addition to systemic effects, resveratrol can enhance GLUT4 translocation via Akt signaling and increase PDH activity in hearts from diabetic animals (40, 201), suggesting that resveratrol may have direct effects to promote myocardial glucose uptake and metabolism in diabetes. As discussed earlier, oxidative stress is a significant contributor to cardiac mitochondrial dysfunction and the pathogenesis of diabetic cardiomyopathy. Evidence shows that resveratrol ameliorates oxidative stress in diabetic cardiomyopathy, in part, by inhibiting ROS production and increasing anti-oxidant capacity, which was associated with improved cardiac function (29, 40, 181, 242, 291). As increased FAO rates also lead to excessive ROS production, it is possible that resveratrol decreases oxidative stress by reducing FAO and increasing glucose utilization (40). In addition to anti-oxidant properties, resveratrol has been shown to improve SERCA2a expression and cardiac function in a mouse model of T1D and restore SERCA2a promoter activity that was otherwise repressed in a high glucose environment (247). The protective effects of resveratrol to restore SERCA2 promoter activity and cardiac function are dependent on inducing silent information regulator (SIRT) 1 expression and activity (247). Several studies have linked activation of SIRT1 and/or SIRT3 by resveratrol to be involved in ameliorating several forms of HF, including diabetic cardiomyopathy (256). Evidence also shows that resveratrol may also reduce oxidative stress through activation of SIRT1 (257). Thus, resveratrol may also prevent or ameliorate diabetic cardiomyopathy by reducing oxidative stress and improving cardiomyocyte Ca2 + -handling via SIRT1 activation and restoring SERCA2a expression and activation. In addition, some studies demonstrate modulation of mitochondrial function by resveratrol in peripheral tissues and suggest that a similar pathway may exist in the heart (10, 146). To date, only a limited number of studies have exam-

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ined the effect of resveratrol on cardiac mitochondrial function, specifically in diabetes. These studies suggest that resveratrol may improve mitochondrial bioenergetics and reduce mitochondrial-derived ROS in diabetes (12). However, further investigation is needed to understand the effects of resveratrol treatment in hearts of obese and diabetic animals, whether resveratrol alters substrate metabolism and mitochondrial function, and ultimately whether this protects against cardiac dysfunction and other features characteristic of diabetic cardiomyopathy. In general, clinical studies of resveratrol for the treatment of CVD are limited, with even fewer focused on diabetes and its complications. To date, only a few clinical studies involving diabetic patients have been completed. These studies report modest reductions in blood glucose levels (19, 29) and improved insulin sensitivity (60, 161, 178). However, this remains controversial due to the wide variance in resveratrol dose, duration of treatment, and age/health of the subjects studied (208, 259). Nevertheless, resveratrol supplementation may be a fruitful avenue for future research using models of diabetic cardiomyopathy and clinical investigation in the diabetic patient population. Recently, it has been demonstrated that resveratrol accumulates in cardiac tissue in a dose and time-dependent manner, which is the first description of its kind (30). In addition, the accumulated tissue level of resveratrol was associated with a long-term improvement in cardiac function in diabetic animals, and almost complete recovery of hemodynamic measures at the highest dose (30). The early stages of diabetic cardiomyopathy characterized by diastolic dysfunction are, in fact, reversible in humans with diabetes who lose weight and normalize metabolism (158). Thus, the pathogenesis of diabetic cardiomyopathy includes this reversible phase, which emphasizes early and aggressive lifestyle modifications in diabetic patients. In this context, there is an opportunity for resveratrol treatment to significantly impact the prognosis of these patients, given that this polyphenol is also characterized as an exercise mimetic (69). While it is not possible to make a definitive conclusion about the clinical application of resveratrol at this time, it is certainly a feasible therapeutic supplement for prevention or management of diabetic cardiomyopathy that merits further investigation (Fig. 6).

FIG. 6. Targets of resveratrol in the treatment of diabetic cardiomyopathy. The naturally occurring polyphenol resveratrol displays multiple systemic and cardiacspecific effects that may be effective in the treatment of diabetic cardiomyopathy, including anti-diabetic, antioxidant, modulation of mitochondrial function, and Ca2 + dynamics.

MITOCHONDRIAL STRESS IN DIABETIC CARDIOMYOPATHY Conclusion

Given that diabetic cardiomyopathy is now recognized to have a high prevalence in the diabetic population, early treatment and screening is optimal to prevent a further decline in cardiac performance. Thorough investigation and understanding of the mechanisms underlying the initiation and progression of diabetic cardiomyopathy has shed considerable light on the important mediators of diabetic cardiomyopathy. It is clear that cardiac insulin resistance and reduced glucose oxidation are early features of diabetes. This, together with increased circulating FA levels result in accelerated FA uptake and FAO and activation of cardiac PPAR-a-mediated gene transcription, which further promotes FA metabolism at the expense of glucose. Over time, mitochondrial dysfunction and impaired cardiac function develops, a phenomenon that is driven by excessive FA uptake, ectopic cardiac lipid accumulation, impaired cytosolic and mitochondrial Ca2 + handling, and increased oxidative stress. All these are key mediators of diabetic cardiomyopathy that contribute to the initiation and exacerbation of this dysfunction. Although drugs that target FA uptake and oxidation have been investigated, current clinical evidence does not yet support approved use of these agents in patients for the treatment of diabetic cardiomyopathy. However, it is possible that the natural polyphenol resveratrol represents an alternative therapeutic strategy to target the multiple pathophysiological factors, which predispose damage to mitochondria as well as targeting facets of mitochondrial function itself. Indeed, experimental data support a role for resveratrol in mitigating mitochondrial damage and the progression of diabetic cardiomyopathy, suggesting that resveratrol may have a promising impact on the future management of diabetic cardiomyopathy by having pleiotropic effects. In summary, diabetic cardiomyopathy remains an important, although sometimes under-appreciated, consequence of obesity and diabetes. Given that CVD is the principal cause of morbidity and mortality among diabetic patients and diabetic cardiomyopathy likely contributes to this, effective therapies for treating diabetic cardiomyopathy may be of tremendous benefit to this growing patient population. Acknowledgments

These authors acknowledge support from Alberta Innovates–Health Solutions (AIHS), Heart and Stroke Foundation of Canada (HSFC), and Canadian Institutes for Health Research (CIHR). References

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Address correspondence to: Dr. Jason R.B. Dyck 458 Heritage Medical Research Centre Department of Pediatrics Cardiovascular Research Centre University of Alberta Edmonton, Alberta T6G 2S2 Canada E-mail: [email protected] Date of first submission to ARS Central, February 24, 2015; date of final revised submission, March 12, 2015; date of acceptance, March 23, 2015.

Abbreviations Used ACSL1 ¼ acyl-CoA synthetase 1 AGEs ¼ advanced glycation endproducts APOO ¼ apolipoprotein O ATGL ¼ adipose triglyceride lipase ATP ¼ adenosine triphosphate Ca2+ ¼ calcium CAD ¼ coronary artery disease CM ¼ chylomicron CPT1 ¼ carnitine palmitoyal transferase 1 CVD ¼ cardiovascular disease DAG ¼ diacylglyercides

eNOS ¼ endothelial nitric oxide synthase ETC ¼ electron transport chain FABP ¼ fatty acid binding protein FAO ¼ fatty acid oxidation FATP1 ¼ fatty acid transport protein 1 FFA ¼ free fatty acid H2 O2 ¼ hydrogen peroxide HF ¼ heart failure HFD ¼ high fat diet hLpLGPI ¼ glycosylphosphatidylinositol anchored human lipoprotein lipase HNE ¼ 4-hydroxy-2-nonenal LPL ¼ lipoprotein lipase LV ¼ left ventricular LVH ¼ left ventricular hypertrophy MCD ¼ malonyl-CoA decarboxylase MHC ¼ myosin heavy chain MVO2 ¼ myocardial oxygen consumption NE ¼ norepinephrine NOS ¼ nitric oxide synthase O2 ¼ oxygen O-GlcNAc ¼ O-linked b-N-acetylglucosamine OXPHOS ¼ oxidative phosphorylation PCr ¼ phosphocreatine PDH ¼ pyruvate dehydrogenase PET ¼ positron emission tomography PGC-1a ¼ peroxisome proliferator-activated receptor c co-activator 1a PPAR-a ¼ peroxisome proliferator-activated receptor-a ROS ¼ reactive oxygen species SERCA ¼ sarcoplasmic reticulum Ca2+-ATPase SIRT ¼ silent information regulator SR ¼ sarcoplasmic reticulum STZ ¼ streptozotocin T1D ¼ type 1 diabetes T2D ¼ type 2 diabetes TAG ¼ triacylglycerol/triglycerides TCA ¼ tricarboxylic acid TnC ¼ troponin C UCP ¼ uncoupling protein UCP-DTA ¼ uncoupling protein-diphtheria toxin A VLDL ¼ very-low-density lipoprotein ZDF ¼ Zucker diabetic fatty rat

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