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

Abstract

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...

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

“…As previously reported by different groups, including our group, ET-1 has been traditionally described as a transcriptional target for the action of TGF-b1 in a number of cells and tissues, 31,32,43 and there are also studies showing the ability of ET-1 to enhance the synthesis of TGF-b1. [34][35][36] The existence of a TGF-b1/ET-1 axis for the promotion of fibrosis, such as the one reported here in the peritoneum, has already been described, for instance, in the fibrotic skin or lung, thus suggesting that it is a recurrent mechanism by which TGF-b1 in cooperation with other factors, such as ET-1, connective tissue growth factor, or angiotensin II, exerts its profibrotic actions. 32,[44][45][46] From a clinical perspective, together with the development of more biocompatible fluids that better preserve the mesothelial cell monolayer, the specific blockade of the TGF-b1 signal transduction pathway may provide an interesting therapeutic approach.…”

“…[31][32][33] Some reports have shown that ET-1 is also able to induce the expression of TGF-b1; these observations indicate the existence of reciprocal regulation of these factors in some cellular contexts. [34][35][36] Concerning the role of ET-1 in peritoneal fibrosis, early studies have shown that volume stress stimulates peritoneal ET-1 release in PD and that increased osmolarity induces collagen type I RNA synthesis in human peritoneal mesothelial cells through a mechanism inhibited by ET receptor blockade. 37,38 Nevertheless, despite the pre-eminent role of ET-1 in fibrogenesis in different pathologic contexts, the contribution of this factor to the development of PD-induced peritoneal impairment remains largely unknown.…”

The role of endothelial–mesenchymal transition in development and pathological process

“…Persistently high plasma endothelin-1 (ET-1) levels in diabetic patients are associated with the development of cardiac fibrosis, which results from the deposition of extracellular matrix and recruitment of fibroblasts (24). Widyantoro et al (25) have confirmed that diabetes mellitus upregulated cardiac ET-1 expression in streptozotocin-induced diabetic mice. Cardiac function was decreased, and perivascular fibrosis was enhanced in diabetic mice.…”

Cardiorenal Syndrome

“…Several wellknown mediators of neurohormonal processes, such as angiotensin II, aldosterone, and endothelin-1, are linked to cardiac and renal fibrosis. [161][162][163][164][165] Marinobufagenin, an endogenous cardiotonic steroid induced by angiotensin II, 166 was recently identified in uremic patients. 167 Increased circulating levels of marinobufagenin in a STNx model have been demonstrated to induce cardiac fibrosis and hypertrophy, and has been shown to impair diastolic function, 168 in association with increased systemic oxidative stress, 169 similar to IS effects.…”