Abstract
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.
Highlights
Diabetes mellitus (DM) can affect cardiac structure and function and lead to heart failure in the absence of atherosclerosis and hypertension, which is called diabetic cardiomyopathy (DCM) [1]
We found that Diabetes mellitus increased cardiac Myocyte enhancer factor 2A (MEF2A) expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via Endothelial-to-mesenchymal transition (EndMT)
These results suggested that MEF2A inhibition could reverse cardiac remodeling in diabetic mice
Summary
Diabetes mellitus (DM) can affect cardiac structure and function and lead to heart failure in the absence of atherosclerosis and hypertension, which is called diabetic cardiomyopathy (DCM) [1]. Myocardial fibrosis is often present in end-stage heart failure caused by DCM. Fibrosis, which is attributed to an excess deposition of extracellular matrix (ECM) components, is one of the most common pathological changes found in various organs, including the heart, the detailed mechanism responsible for this change remains unclear. EndMT is stimulated by TGF-β2 through Smad, MEK (MAPK [mitogen-activated protein kinase]/ERK [extracellular signal-regulated kinase]), PI3K (phosphoinositide3-kinase), and p38 MAPK signaling pathways. Inhibitors of these pathways prevent TGF-β2induced EndMT [4]. The factors regulating EndMT under pathologic conditions of high glucose are not clear and remain to be elucidated
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