Endothelial Cell-Derived Endothelin-1 Promotes Cardiac Fibrosis in Diabetic Hearts Through Stimulation of Endothelial-to-Mesenchymal Transition
Endothelial Cell-Derived Endothelin-1 Promotes Cardiac Fibrosis in Diabetic Hearts Through Stimulation of Endothelial-to-Mesenchymal Transition
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DOI：
10.1161/circulationaha.110.938217
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发表时间：
2010-06-08
期刊：
影响因子：
37.8
通讯作者：
Hirata, Ken-ichi
中科院分区：
文献类型：
--
作者：
Widyantoro, Bambang;Emoto, Noriaki;Hirata, Ken-ichi
背景-糖尿病患者持续高的血浆内皮素-1(ET-1)水平与心脏纤维化的发生有关，其原因是细胞外基质的沉积和成纤维细胞的募集，其来源尚不清楚。然而，潜在的机制仍然难以捉摸。在这里，我们假设ET-1可能通过血管内皮细胞向间充质细胞的转变在糖尿病心脏中参与心脏成纤维细胞的积聚。方法和结果-我们使用毒素链脲佐菌素诱导血管内皮细胞特异性ET-1基因敲除[ET-1(f/f)；Tie2-Cre(+)]小鼠及其野生型小鼠糖尿病。在糖尿病诱导后8、24和36周检测基因表达及组织学和功能参数。糖尿病增加了野生型小鼠心脏ET-1的表达，通过产生超氧化物导致线粒体破裂和肌原纤维紊乱。糖尿病小鼠还表现出心脏微血管形成障碍和心脏血管内皮生长因子表达减少。ET-1通过内皮细胞向间充质细胞的转化促进成纤维细胞的积聚，进一步促进心脏纤维化和心力衰竭。所有这些特征在ET-1(f/f)和Tie2-Cre(+)心脏中被取消。通过小干扰RNA靶向沉默培养的人内皮细胞中的ET-1基因，通过抑制转化生长因子-β信号的激活和保存内皮细胞-细胞接触调节因子VE-cadherin，改善了高糖诱导的表型转换和成纤维细胞标志物的获得。结论--这些结果提供了新的见解，表明糖尿病诱导的心脏纤维化与内皮细胞的成纤维细胞的出现有关，并且这一内皮细胞到间质的转换过程是由ET-1刺激的。靶向内皮细胞来源的ET-1可能有助于预防糖尿病心肌病。(发行量。2010；121：2407-2418。)
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 (+)] 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 (+) 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-beta 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.)