Contributions of endothelin‐1 and sodium hydrogen exchanger‐1 in the diabetic myocardium

Hileeto, Denise; Cukiernik, Mark; Mukherjee, Shankar; Evans, Terry; Barbin, Yousef P.; Downey, Dónal B.; Karmazyn, Morris; Chakrabarti, Subrata

doi:10.1002/dmrr.322

Cited by 44 publications

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“…The same study also demonstrated the alteration of several microRNAs (miRNAs) in EndMT of nondiabetic etiology (5). We previously demonstrated EndMT in the retina of diabetic animals (8) as well as a pathogenetic role of endothelin 1 (ET-1) in diabetic cardiomyopathy (3,4). Of note, ET-1 has been demonstrated to be of significance in EndMT in the diabetic heart (9).…”

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confidence: 88%

“…Endothelial cells (ECs) are initial targets of hyperglycemic damage and play a major role in the production of ECM proteins in all chronic diabetic complications. At the structural level in the heart, such changes are manifested as thickening of the capillary basement membrane, focal myocardial fibrosis, and so forth (3,4). A result of sustained injury in the fibrotic diseases is that ECs undergo a process of transdifferentiation (i.e., endothelial-to-mesenchymal transition [EndMT]) (5,6).…”

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confidence: 99%

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miR-200b Mediates Endothelial-to-Mesenchymal Transition in Diabetic Cardiomyopathy

et al. 2015

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Hyperglycemia-induced endothelial injury is a key pathogenetic factor in diabetic cardiomyopathy. Endothelial injury may lead to a phenotypic change (i.e., endothelial-to-mesenchymal transition [EndMT]), causing cardiac fibrosis. Epigenetic mechanisms, through specific microRNA, may regulate such a process. We investigated the mechanisms for such changes in cardiac microvascular endothelial cells and in the heart of genetically engineered mice with chemically induced diabetes. Cardiac tissues and isolated mouse heart endothelial cells (MHECs) from animals with or without endothelial-specific overexpression of miR-200b, with or without streptozotocin-induced diabetes, were examined at the mRNA and protein levels for endothelial and mesenchymal markers. Expression of miR-200b and its targets was quantified. Cardiac functions and structures were analyzed. In the hearts of wild-type diabetic mice, EndMT was observed, which was prevented in the miR-200b transgenic diabetic mice. Expression of specific markers such as vascular endothelial growth factor, zinc finger E-box–binding homeobox, transforming growth factor-β1, and p300 were increased in the hearts of diabetic mice and were prevented following miR-200b overexpression. MHECs showed similar changes. miR-200b overexpression also prevented diabetes-induced cardiac functional and structural changes. These data indicate that glucose-induced EndMT in vivo and in vitro in the hearts of diabetic mice is possibly mediated by miR-200b and p300.

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confidence: 88%

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miR-200b Mediates Endothelial-to-Mesenchymal Transition in Diabetic Cardiomyopathy

et al. 2015

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Section: Clinical Perspective On P 2418mentioning

confidence: 99%

“…Recently, the benefit of endothelin receptor antagonist in attenuating diabetes mellitus-induced myocardial dysfunction in experimental studies was reported. [12][13][14][15][16][17][18] Most of the aforementioned studies demonstrate attenuation of fibrosis, restoration of vascular hyperactivity, and improvement of cardiac function as the important features of ET-1 receptor blockade; however, such pharmacology-based studies are not able to identify the molecular mechanism linking ET-1 to diabetic cardiomyopathy.Homozygous deletion of ET-1 in mice is a useful approach for investigating ET-1 signaling in embryonic development; however, early postnatal lethality caused by craniofacial abnormalities precludes the use of these mice in exploring the role of ET-1 in adult physiology. 19 Previously, using the Cre-loxP recombinase system, we generated mice with conditional knockout of ET-1 exclusively in endothelial cells (Y.Y.K.…”

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Endothelial Cell–Derived Endothelin-1 Promotes Cardiac Fibrosis in Diabetic Hearts Through Stimulation of Endothelial-to-Mesenchymal Transition

et al. 2010

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Background-Persistently high plasma endothelin-1 (ET-1) levels in diabetic patients have been associated with the development of cardiac fibrosis, which results from the deposition of extracellular matrix and fibroblast recruitment from an as-yet unknown source. The underlying mechanism, however, remains elusive. Here, we hypothesize that ET-1 might contribute to the accumulation of cardiac fibroblasts through an endothelial-to-mesenchymal transition in diabetic hearts. Methods and Results-We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout [ET-1 f/f ;Tie2-Cre (ϩ)] mice and their wild-type littermates using the toxin streptozotocin. Gene expression and histological and functional parameters were examined at 8, 24, and 36 weeks after the induction of diabetes mellitus. Diabetes mellitus increased cardiac ET-1 expression in wild-type mice, leading to mitochondrial disruption and myofibril disarray through the generation of superoxide. Diabetic mice also showed impairment of cardiac microvascularization and a decrease in cardiac vascular endothelial growth factor expression. ET-1 further promotes cardiac fibrosis and heart failure through the accumulation of fibroblasts via endothelial-to-mesenchymal transition. All of these features were abolished in ET-1 f/f ;Tie2-Cre (ϩ) hearts. Targeted ET-1 gene silencing by small interfering RNA in cultured human endothelial cells ameliorated high glucose-induced phenotypic transition and acquisition of a fibroblast marker through the inhibition of transforming growth factor-␤ signaling activation and preservation of the endothelial cell-to-cell contact regulator VE-cadherin. Conclusions-These results provide new insights suggesting that diabetes mellitus-induced cardiac fibrosis is associated with the emergence of fibroblasts from endothelial cells and that this endothelial-to-mesenchymal transition process is stimulated by ET-1. Targeting endothelial cell-derived ET-1 might be beneficial in the prevention of diabetic cardiomyopathy. (Circulation. 2010;121:2407-2418.)Key Words: cardiomyopathy Ⅲ diabetes mellitus Ⅲ endothelin Ⅲ fibrosis Ⅲ heart failure D iabetes mellitus can affect cardiac structure and function, and this may lead to heart failure in the absence of coronary atherosclerosis and hypertension. However, despite the importance of this clinical entity, the multifactorial nature of the disease remains incompletely understood. Three decades have passed since Rubler et al 1 first described patients with diabetic cardiomyopathy, and to date, a number of epidemiological, clinical, and experimental studies have confirmed the existence of this unique cardiomyopathy. 2,3 Several mechanisms are considered to be important in the development of cardiac structural and ultrastructural changes, with hyperglycemia and altered cardiac metabolism being proposed as central to the pathophysiology of this disorder. 4 Given the increased risk of heart failure and cardiovascular events in diabetic patients, a better understanding of the underlying mechanisms...

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“…Diabetes-induced capillary basement membrane thickening, increased extracellular matrix (ECM) protein synthesis, and blood flow alterations in the heart are prevented by ET-receptor antagonism [8]. Studies have also suggested that the mechanism of ET-1 action in the heart may involve sodium hydrogen exchanger (NHE) [13]. Evidence from a variety of experimental models show that the cardiac effects of ET-1 may be mediated through the activation of Na + /H + exchange [14,15].…”

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Role of endothelin‐1, sodium hydrogen exchanger‐1 and mitogen activated protein kinase (MAPK) activation in glucose‐induced cardiomyocyte hypertrophy

Chen

Khan

Karmazyn

et al. 2006

Diabetes Metabolism Res

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Contributions of endothelin‐1 and sodium hydrogen exchanger‐1 in the diabetic myocardium

Abstract: These results indicate an important contribution of both ET-1 and NHE-1 in the pathogenesis of diabetic cardiomyopathy. These data suggest that NHE-1 may act as a downstream mediator in the production of ET-induced functional and structural changes in the myocardium in diabetes.

Cited by 44 publications

References 58 publications

miR-200b Mediates Endothelial-to-Mesenchymal Transition in Diabetic Cardiomyopathy

miR-200b Mediates Endothelial-to-Mesenchymal Transition in Diabetic Cardiomyopathy

Endothelial Cell–Derived Endothelin-1 Promotes Cardiac Fibrosis in Diabetic Hearts Through Stimulation of Endothelial-to-Mesenchymal Transition

Role of endothelin‐1, sodium hydrogen exchanger‐1 and mitogen activated protein kinase (MAPK) activation in glucose‐induced cardiomyocyte hypertrophy

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