Inhibition of myocyte-specific enhancer factor 2A improved diabetic cardiac fibrosis partially by regulating endothelial-to-mesenchymal transition
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Xue-ying Chen1,*, Rui-juan Lv2,*, Wei Zhang1, Yu-gang Yan4, Peng Li3, Wen-qian Dong1, Xue Liu1, Er-shun Liang1, Hong-liang Tian1, Qing-hua Lu5, Ming-xiang Zhang1
1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China
2Department of Emergency, Qilu Hospital of Shandong University, Jinan, Shandong, China
3College of Pharmacy, Xinxiang Medical University, Xinxiang, China
4Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Jinan, Shandong, China
5Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong, China
*These authors have contributed equally to this work
Ming-Xiang Zhang, e-mail: email@example.com
Qing-hua Lu, e-mail: firstname.lastname@example.org
Keywords: myocyte-specific enhancer factor 2A, fibrosis, diabetes mellitus, endothelial mesenchymal transition
Received: September 29, 2015 Accepted: March 31, 2016 Published: April 20, 2016
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.
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