Cardiac dysfunction in diabetes

Cardiac dysfunction in diabetes

Life Sciences 92 (2013) 599–600 Contents lists available at SciVerse ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie ...

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Life Sciences 92 (2013) 599–600

Contents lists available at SciVerse ScienceDirect

Life Sciences journal homepage: www.elsevier.com/locate/lifescie

Editorial

Cardiac dysfunction in diabetes

Diabetes is a complex, poorly understood disease that has reached epidemic levels worldwide, with impact on multiple organ systems. Based upon 2011 statistics, nearly 26 million people in the United States are diabetic, with an additional 70 million classified as pre-diabetic (CDC Diabetes Fact Sheet, 2011). This epidemic rise in diabetes rates has no indication of reducing; on the contrary, evidence indicates that diabetes is on the rise in the young, with roughly 1 in 400 adolescents newly diagnosed with diabetes. There is no denying the link between diabetes and cardiac dysfunction, as diabetic cardiomyopathy is a well-known consequence of sustained diabetes (Kamalesh, 2007; Witteles and Fowler, 2008; Miki et al., 2012; Murarka and Movahed, 2010). Nearly 70% of diabetes-related deaths are linked to heart disease, with diabetics suffering a two- to four-fold greater death rate due to heart disease than non-diabetics (CDC Diabetes Fact Sheet, 2011). Despite these sobering clinical statistics, there is still little understanding of how diabetes impacts cardiac function. However, studies indicate that diabetes adversely affects many aspects necessary for proper cardiac function, including cardiomyocyte metabolism, pro-survival signaling and calcium handling, and also induces vascular and cardiac fibrosis (Kamalesh, 2007; Kota et al., 2011; Law et al., 2012; Ban and Twigg, 2008; Wold et al., 2005; Wold et al., 2012). In this special issue of Life Sciences, we present a collection of mini-reviews and original research articles by leading experts in the field focused on diabetic cardiac dysfunction. Our first two reviews on the pathogenesis of type 2 diabetic cardiomyopathy are focused on metabolic remodeling and potential novel therapeutic targets. First, Mandavia et al. (2012) discuss emerging molecular and metabolic pathways underlying cardiac dysfunction in diabetes, including the role of adipokines, inflammation, the renin angiotensin aldosterone system, oxidant and endoplasmic reticular (ER) stress, disrupted calcium homeostasis, and endothelial cell dysfunction (Mandavia et al., current issue). Second, Hill (2012) summarizes the latest research on the development of diabetic cardiomyopathy including the role of transcription factors (FOXO) and kinases (mTOR, Pim-1, and p53), as well as the role of ER stress, autophagy, adipokines, and microRNAs (Hill, current issue). Cardiomyocyte loss in the diabetic heart can occur through apoptosis, necrosis and autophagy. Mellor et al. (2012) present a review on the pro-autophagic character of the diabetic heart, which indicates that this pro-survival cellular mechanism contributes to cardiac myocyte loss and dysfunction (Mellor et al., current issue). Understanding how pro-autophagic mechanisms are influenced by diabetes may provide additional clues to the pathogenesis of diabetic cardiomyopathy and new treatment and prevention strategies. Protein modification by O-linked N-acetyl-glucosamine (O-GlcNAc) is increased in diabetes. McLarty et al. (2012) provide a review on how this O-GlcNAc modification may promote dysfunction in the diabetic 0024-3205/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.lfs.2012.11.002

heart through metabolic dysregulation, and interfering with stress responses and calcium handling in cardiomyocytes (McLarty et al., current issue). A newly described role for O-GlcNAc modification in epigenetic regulation is also presented. The primary function of the galanin peptide family and their associated G-protein receptors is largely unknown; however, recent evidence indicates that these pleiotropic peptides may play a role in the pathology of multiple diseases, including diabetes, cancer and Alzheimer's (Counts et al., 2010; Rauch and Kofler, 2010; Legakis, 2005; Lang et al., 2007). Fang et al. (2012) present a review on the developing role of galanin in diabetic cardiomyopathy (Fang et al., current issue). In addition to the above mini-reviews, seven original research articles are presented, focused on mechanisms responsible for diabetic cardiomyopathy. Zhao et al. (2012) present a human study on the efficacy of trimetazidine, an anti-ischemic drug often used to treat angina, to improve cardiac function in diabetic patients (Zhao et al., current issue). Trimetazadine blocks fatty acid metabolism and improves glucose usage by the heart. Their findings indicate that following 6 months of treatment, patients treated with trimetazadine had improved systolic function, which was also linked to increased exercise tolerance and a reduction in inflammatory markers. Using a mouse infarction model, Mohammadzadeh et al. (2012) investigated the role of S100B, a RAGE ligand, in post-infarct remodeling in the diabetic heart (Mohammadzadeh et al., current issue). S100B knockout mice with diabetes exhibited greater dilation and worsened cardiac function post myocardial infarction, which was attributed to increased AGE formation and reduced GLUT4 expression. Research articles by Marsh et al. (2012) and Bennett et al. (2012) both evaluate unique roles for O-GlcNAc in diabetic cardiac dysfunction. First, Marsh et al. (2012) present their findings that beclin-1 and Bcl-2, mediators of autophagy and apoptosis, are targets for O-GlcNAc in the diabetic heart (Marsh et al., current issue). Their results suggest that acylation by O-GlcNAc increases the susceptibility of cardiac myocytes to hemodynamic stress, potentially promoting diabetic cardiomyopathy. Second, Bennett et al. (2012) found that exercised diabetic mice had improved cardiac function associated with reduced protein O-GlcNAcylation in the heart, a finding consistent with their previous data in non-diabetic mice (Bennett et al., current issue). Mitochondrial dysfunction has been implicated in diabetic cardiomyopathy, but little is known about the specific mechanisms involved. Fancher et al. (2012) evaluated the effects of diabetes on function and expression of ATP-dependent K + channels in cardiac mitochondria (mitoKATP). Their findings indicate that diabetes reduced the expression of mitoKATP channels and negatively impacted function by a reduction in Kir6.1 and SUR1, key subunits of mitoKATP (Fancher et al., current issue). In the final manuscript, Fowlkes et al. (2012) assess the phenotype and function of cardiac fibroblasts from Zucker

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diabetic and lean control rats (Fowlkes et al., current issue). Fibroblasts from diabetic hearts exhibited enhanced collagen expression and contractile function, along with myofibroblast cell markers. Their data indicate that diabetic cardiomyopathy and associated fibrosis may be attributed to the transformation of cardiac fibroblasts into a pro-fibrotic phenotype. As shown in the manuscripts presented in this special issue, it is clear that diabetes negatively influences cardiac function by multiple mechanisms including alterations in cell survival pathways, extracellular matrix production, post-translation protein modification, and glucose metabolism. Further study is necessary to understand the effects of diabetes on the heart, and for the advancement of clinical strategies to improve treatments for diabetic cardiomyopathy. References Ban CR, Twigg SM. Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag 2008;4(3):575–96. Bennett CE, Johnsen VL, Shearer J, Belke D. Exercise training mitigates aberrant cardiac protein O-GlcNAcylation in streptozotocin-induced diabetic mice. Life Sci SI 2012. Centers for Disease Control, Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011. Counts SE, Perez SE, Ginsberg SD, Mufson EJ. Neuroprotective role for galanin in Alzheimer's disease. EXS 2010;102:143–62. Fancher IS, Dick G, Hollander JM. Diabetes mellitus reduces the function and expression of ATP-dependent K+ channels in cardiac mitochondria. Life Sci SI 2012. Fang P, Sun J, Wang X, Zhang Z, Bo P, Shi M. Galanin participates in the functional regulation in the diabetic heart. Life Sci SI 2012. Fowlkes V, Clark J, Fix C, Morales MO, Qiao X, Goldsmith JG, et al. Diabetic environment promotes a myofibroblast phenotype in cardiac fibroblasts. Life Sci SI 2012. Hill JA. Diabetic cardiomyopathy and metabolic remodeling of the heart. Life Sci SI 2012. Kamalesh M. Heart failure in diabetes and related conditions. J Card Fail 2007;13(10): 861–73. Kota SK, Kota SK, Jammula S, Panda S, Modi KD. Effect of diabetes on alteration of metabolism in cardiac myocytes: therapeutic implications. Diabetes Technol Ther 2011;13(11):1155–60. Lang R, Gundlach AL, Kofler B. The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol Ther 2007;115(2):177–207.

Law B, Fowlkes V, Goldsmith JG, Carver W, Goldsmith EC. Diabetes-induced alterations in the extracellular matrix and their impact on myocardial function. Microsc Microanal 2012;18(1):22–34. Legakis IN. The role of galanin in metabolic disorders leading to type 2 diabetes mellitus. Drug News Perspect 2005;18(3):173–7. Mandavia CH, Aroor AR, DeMarco VG, Sowers J. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci SI 2012. Marsh SA, Powell PC, Dell'Italia LJ, Chatham JC, Phil D. Cardiac O-GlcNAcylation blunts autophagic signaling in the diabetic heart. Life Sci SI 2012. McLarty JL, Marsh SA, Chatham JC. Post-translational protein modification by O-linked N-acetyl-glucosamine: its role in mediating the adverse effects of diabetes on the heart. Life Sci SI 2012. Mellor KM, Reichelt ME, Delbridge LM. Autophagic predisposition in the insulin resistant diabetic heart. Life Sci SI 2012. Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev in press, http://dx.doi.org/10.1007/s10741-012-9313-3 [published online 28 March 2012] [PMID:22453289]. Mohammadzadeh F, Desjardins J, Proteau G, Tsoporis JN, Leong-Poi H, Parker T. S100B: role in cardiac remodeling and function following myocardial infarction in diabetes. Life Sci SI 2012. Murarka S, Movahed MR. Diabetic cardiomyopathy. J Card Fail 2010;16(12):971–9. Rauch I, Kofler B. The galanin system in cancer. EXS 2010;102:223–41. Witteles RM, Fowler MB. Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options. J Am Coll Cardiol 2008;51(2):93-102. Wold LE, Dutta K, Mason MM, Ren J, Cala SE, Schwanke ML, et al. Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats. J Mol Cell Cardiol 2005;39(2):297–307. Wold LE, Lucchesi PA, Schaffer SW. Vascular dysfunction in diabetes. Vascul Pharmacol 2012;57(5–6):131–2. Zhao P, Zhang J, Yin X, Maharaj P, Narraindoo S, Cui L, et al. The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated cardiomyopathy. Life Sci SI 2012.

J.D. Gardner⁎ D.B. Murray L.E. Wold Louisiana State University Health Sciences Center, Department of Physiology, 1901 Perdido St., MEB 7205, New Orleans, LA 70112, USA ⁎Corresponding author. Tel.: + 1 504 568 7252; fax: +1 504 568 6158. E-mail address: [email protected] (J.D. Gardner).