MinireviewDiabetic cardiomyopathy and metabolic remodeling of the heart
Introduction
The incidence and prevalence of diabetes mellitus (DM) are both rising rapidly (Roger et al., 2012). DM affects 350 million people around the world, and the WHO has projected that diabetes deaths will double between 2005 and 2030 (http://www.who.int/diabetes/en/). Within this rapidly expanding public health epidemic of worldwide proportions, type 2 DM (T2DM) accounts for 90–95% of all diagnosed diabetes in adults (Roger et al., 2012). Patients with diabetes are at increased risk for developing coronary artery disease (CAD), hypertension, and heart failure (HF), and the majority of these patients succumb ultimately to heart disease. However, despite the importance of heart disease-promoting comorbidities, ventricular dysfunction and a clinical syndrome of HF can develop independent of underlying CAD, a condition termed “diabetic cardiomyopathy” (Rubler et al., 1972). Indeed, epidemiological studies demonstrate that obesity and diabetes are critical risk factors for cardiovascular disease, independent of blood pressure and coronary atherosclerosis (Grundy, 2012). Diabetic cardiomyopathy and the other diabetes-associated cardiovascular risks are the leading cause of morbidity and mortality in these individuals.
T2DM is typified by hyperglycemia, hyperinsulinemia and obesity, and insulin resistance is a cardinal feature (Witteles and Fowler, 2008). At later stages of disease, some patients manifest insufficient insulin action. Together, these events, acting through a variety of mediators such as altered intracellular calcium, increased reactive oxygen species (ROS), ceramides, hexosamines, advanced glycation end products, and more, contribute to the pathogenesis of the disorder (Battiprolu et al., 2010). Additionally, the interplay between dysregulated function of endothelial cells and fibroblasts contributes, highlighting the multifactorial etiology of diabetic cardiomyopathy. Now, metabolic derangements within the cardiomyocyte itself are emerging as important elements in the pathogenesis of the disorder.
Cardiomyocytes are capable of metabolizing a spectrum of substrates. These “metabolic omnivores” normally rely on fatty acids and glucose, and to a lesser extent lactate and ketone bodies, to produce ATP (Hue and Taegtmeyer, 2009). These substrates, however, are unable to enter the cardiomyocyte by simple diffusion and must be taken up by facilitated transport. Fatty acid uptake is mediated by FAT (fatty acid translocase, also known as cluster of differentiation 36, CD36), and glucose intake is accomplished by GLUT4 (glucose transporter type 4). In response to availability of nutrients or increased cardiac work, plasma insulin concentrations rise (Schwenk et al., 2008). This, in turn, provokes GLUT4 as well as FAT/CD36 translocation to the myocyte sarcolemma. To date, many studies have implicated signaling pathways that regulate GLUT4 translocation with those involved in transport of FAT/CD36 to the sarcolemma (Schwenk et al., 2008, Steinbusch et al., 2011). However, during the development of insulin resistance and T2DM, FAT/CD36 becomes preferentially sarcolemma-localized, whereas GLUT4 is internalized. This reciprocal positioning of GLUT4 and FAT/CD36 is central to aberrant substrate uptake in the diabetic heart, where fatty acid metabolism is chronically increased at the expense of glucose (Schwenk et al., 2008, Steinbusch et al., 2011). In addition, the interplay of preferential substrate utilization is impacted by a variety of other mediators, as previously reviewed (Battiprolu et al., 2010).
Dissection of the pathophysiology of diabetic cardiomyopathy and disease-related metabolic remodeling in the heart has progressed considerably in recent years. As a result, several novel mechanisms have emerged. Here, we highlight several of these molecular targets (graphical abstract, Fig. 1), acknowledging that space limitations and the scope of this review do not allow us to discuss them all.
Section snippets
Forkhead transcription factors
FoxO (forkhead box-containing protein, O subfamily) proteins are emerging as important targets of insulin and other growth factor action in the myocardium (Ferdous et al., 2010, Ronnebaum and Patterson, 2010). Abundant evidence demonstrates that three members of the FoxO subfamily (FoxO1, -3, -4) are critical to maintenance of cardiac function and stress responsiveness (Ferdous et al., 2010, Ronnebaum and Patterson, 2010). FoxO transcription factors regulate cardiac growth and govern insulin
Mammalian target of rapamycin
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that regulates cell growth and metabolism and is dysregulated in cancer and DM (Laplante and Sabatini, 2009, Zoncu et al., 2011). mTOR comprises two multiprotein complexes: mTORC1, which regulates pathways involved in mRNA translation and autophagy, and mTORC2, which regulates insulin signaling and other cellular processes. Insulin and insulin-like growth factors (IGFs) are major mTOR activators that signal through
MicroRNAs
MicroRNAs (miRNAs or miRs) are naturally occurring, small noncoding single-strand RNAs that regulate gene expression usually by targeting mRNAs for degradation or by repressing protein translation. In some cases, miRNAs up-regulate translation of some mRNAs, especially during cell cycle arrest or in terminally differentiated cells (Vasudevan et al., 2007). miRNAs have been identified as important molecular regulators participating in many biological functions. However, their actions are complex
Pim-1
In addition to altered calcium homeostasis, down-regulation of prosurvival signaling factors has also been implicated in diabetic cardiomyopathy (Katare et al., 2011). Pim-1 (proviral integration site for Moloney murine leukemia virus-1) is a serine/threonine protein kinase that modulates SERCA and promotes cardiomyocyte survival and function (Katare et al., 2011, Muraski et al., 2007). Pim-1 is upregulated in failing hearts, potentially as an inefficient, last-ditch attempt to preserve cardiac
Mitochondrial dysfunction
Mitochondrial dysfunction contributes to progression of diabetes and diabetic cardiomyopathy (Duncan, 2011). The transcription factor p53 is induced by ischemia, chronic pressure overload, or metabolic disturbances. A recent report suggests that p53 contributes to cardiac dysfunction in diabetes by promoting mitochondrial oxygen consumption, ROS production, and lipid accumulation (Nakamura et al., 2012). The SCO2 (synthesis of cytochrome c oxidase 2) gene is a transcriptional target of p53, and
Unfolded protein response
Accumulating evidence points to disruption of endoplasmic reticulum (ER) homeostasis in diabetic cardiomyopathy (Ceylan-Isik et al., 2011, Li et al., 2010, Miki et al., 2009, Wu et al., 2011). The ER is the central organelle for secretory/transmembrane protein folding, calcium storage, and lipid synthesis. Elevated demand for synthesis of new proteins and lipids poses a special burden on the ER. When the throughput of proteins being processed in the ER exceeds folding capacity, “ER stress”
Adipokines
Adipose tissue expansion is, of course, a hallmark of obesity. Over the past 20 years, our view of adipose tissue has been revolutionized from previously being viewed as an inert energy storage tissue now to clear recognition of its role as the largest endocrine organ in the body (Scherer, 2006). Beside fatty acids, adipocytes synthesize and secrete a host of proteins, including adiponectin, leptin, resistin, tumor necrosis factor alpha (TNFα) interleukin-6 (IL-6), and many more, collectively
Metabolic role of autophagy
Autophagy is an evolutionarily ancient process of intracellular protein and organelle recycling (Yang and Klionsky, 2010). Faced with nutrient deprivation, most cells manifest a complex autophagic response that initiates with the formation of an intracellular membrane organelle that engulfs cytoplasmic material forming an autophagosome. After fusion with a lysosome, the intra-autophagosomal cargo is digested and the resulting degradation products are released to provide nutrients and cellular
Conclusions and perspective
HF has remained the leading cause of death in industrialized nations for some years. Numerous events contribute to the rise in HF, but the increasing prevalence of DM is an important contributor. Derangements in insulin signaling have widespread and devastating effects in numerous tissues, including the cardiovascular system. The multiple, interlacing events occurring in patients with diabetes culminate in an environment which, coupled with insulin resistance, leads to diabetic cardiomyopathy.
Conflict of interest statement
The authors have declared that no conflicts of interest exist.
Acknowledgments
This work was supported by grants from the NIH (HL-075173, J.A.H.; HL-080144, J.A.H.; HL-090842, J.A.H.), AHA (0640084N, J.A.H.; 12POST9030041, P.K.B.), ADA mentor-based postdoctoral fellowship (7-08-MN-21-ADA, J.A.H. and P.K.B.), the AHA-Jon Holden DeHaan Foundation (0970518N, J.A.H.), and the Fondo Nacional de Desarrollo Cientifico y Tecnologico: FONDECYT 1120212 and ACT1111 (S.L.). C.L.C. is a recipient of a CONICYT fellowship, Chile.
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