Diabetic cardiomyopathy: signaling defects and therapeutic approaches

Dobrin, J.; Lebeche, Djamel

doi:10.1586/erc.10.17

Cited by 57 publications

(53 citation statements)

References 215 publications

(245 reference statements)

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“…The diabetic heart relies on FA oxidation and is unable to switch to glucose, despite the lower oxygen consumption requirement of that substrate. As a consequence, cardiac efficiency (the ratio of cardiac work to myocardial oxygen consumption) decreases; diminished cardiac efficiency has been reported in humans and experimental animals with diabetes (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

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Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

et al. 2012

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The leading cause of death in diabetic patients is cardiovascular disease; diabetic cardiomyopathy is typified by alterations in cardiac morphology and function, independent of hypertension or coronary disease. However, the molecular mechanism that links diabetes to cardiomyopathy is incompletely understood. Insulin resistance is a hallmark feature of diabetes, and the FoxO family of transcription factors, which regulate cell size, viability, and metabolism, are established targets of insulin and growth factor signaling. Here, we set out to evaluate a possible role of FoxO proteins in diabetic cardiomyopathy. We found that FoxO proteins were persistently activated in cardiac tissue in mice with diabetes induced either genetically or by high-fat diet (HFD). FoxO activity was critically linked with development of cardiomyopathy: cardiomyocyte-specific deletion of FoxO1 rescued HFD-induced declines in cardiac function and preserved cardiomyocyte insulin responsiveness. FoxO1-depleted cells displayed a shift in their metabolic substrate usage, from free fatty acids to glucose, associated with decreased accumulation of lipids in the heart. Furthermore, we found that FoxO1-dependent downregulation of IRS1 resulted in blunted Akt signaling and insulin resistance. Together, these data suggest that activation of FoxO1 is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease.

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Section: Discussionmentioning

confidence: 99%

“…Insulin resistance is defined as diminished insulin-dependent stimulation of myocardial glucose uptake (42)(43)(44)(45). Underlying mechanisms include FA accumulation that impairs insulin-mediated glucose uptake through inhibition of IRS and Akt.…”

Section: Discussionmentioning

confidence: 99%

Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

et al. 2012

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“…Specific therapeutic and preventive measures for diabetic cardiomyopathy are currently lacking [32]. The mechanism by which high blood glucose damages myocardial tissues to cause the disease and the factors that influence this pathogenic process remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

2013

J Diabetes Metab

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High glucose-induced oxidative stress is a major contributing mechanism to the development of diabetic cardiomyopathy. Nrf2 is an emerging critical regulator of cellular defense against oxidative damage. The role of Nrf2 in diabetic cardiomyopathy was investigated in vivo. Streptozotocin (STZ) induced diabetes in Nrf2 knockout (KO) mice that rapidly progressed to severe conditions with high mortality within two weeks of injection; whereas, in wild type (WT) mice, diabetes was less severe with no death. Severe myocardial lesions were observed in diabetic KO mice that had high, sublethal levels of blood glucose including: (a) irregular myocardial arrangements, myofibrillar discontinuation, and cell death; (b) reduced electron density, discontinuation of myocardial fibers, and mitochondrial damage; and (c) markedly reduced contractility of the cardiomyocytes to β-agonist stimulation. Parallel to severe cardiomyopathy, the diabetic KO hearts showed: (a) increased apoptosis as revealed by TUNEL and PARP1 cleavage assays; (b) infiltration of granulocytes and macrophages as well as fibrosis indicating robust inflammatory response; and (c) heightened oxidative stress as evidenced by increased levels of 8-hydroxydeoxyquanine, free malondialdehyde, and 3-nitrotyrosine. Increased oxidative stress in the KO hearts was attributed to decrease or loss of the basal and induced expression of Nrf2-dependent cytoprotective genes. Our findings demonstrate that loss of Nrf2 function synergizes with high glucose to cause heightened oxidative stress in the heart leading to severe diabetic cardiomyopathy.

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“…The development of diabetic myocardial disease is multifactorial. The main pathophysiological mechanisms that are implicated are possibly as follows: the deficiency of energy utilization in myocardial cells, hypertrophy and fibrosis, microvascular remodeling, homeostatic disorders of calcium, the abnormal activation of the neurohormonal axis, the overexpression of the inflammatory process, and oxidative stress (20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Diastolic function of the right ventricle is impaired in experimental type 2 diabetic rat models

Miao¹,

Zhang²,

Yuan³

et al. 2014

Turk J Med Sci

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Diabetic cardiomyopathy: signaling defects and therapeutic approaches

Cited by 57 publications

References 215 publications

Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

Disruption of Nrf2 Synergizes with High Glucose to Cause Heightened Myocardial Oxidative Stress and Severe Cardiomyopathy in Diabetic Mice

Diastolic function of the right ventricle is impaired in experimental type 2 diabetic rat models

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