Inhibition of myocyte-specific enhancer factor 2A improved diabetic cardiac fibrosis partially by regulating endothelial-to-mesenchymal transition

• Published in: Oncotarget Vol. 7; no. 21; pp. 31053 - 31066
• Main Authors: Chen, Xue-Ying, Lv, Rui-Juan, Zhang, Wei, Yan, Yu-Gang, Li, Peng, Dong, Wen-Qian, Liu, Xue, Liang, Er-Shun, Tian, Hong-Liang, Lu, Qing-Hua, Zhang, Ming-Xiang
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 24.05.2016
• Subjects: Animals; Cells, Cultured; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - therapy; Epithelial-Mesenchymal Transition; Fibrosis - genetics; Fibrosis - metabolism; Fibrosis - pathology; Fibrosis - therapy; Human Umbilical Vein Endothelial Cells; Humans; Male; MEF2 Transcription Factors - antagonists & inhibitors; MEF2 Transcription Factors - biosynthesis; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; Mice; Mice, Inbred C57BL; Myocardium - metabolism; Myocardium - pathology; Research Paper; Signal Transduction; Transfection; endothelial mesenchymal transition; diabetes mellitus; fibrosis; myocyte-specific enhancer factor 2A
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8842

Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose-induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2.