RESUMEN
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.
Asunto(s)
Diabetes Mellitus Experimental/terapia , Fibrosis/terapia , Factores de Transcripción MEF2/antagonistas & inhibidores , Miocardio/patología , Animales , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Transición Epitelial-Mesenquimal , Fibrosis/genética , Fibrosis/metabolismo , Fibrosis/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Factores de Transcripción MEF2/biosíntesis , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Transducción de Señal , TransfecciónRESUMEN
In the title compound, C(14)H(16)ClN(3)O(2)S, the dihedral angle between the 4-chloro-phenyl and 1,3,4-oxadiazole rings is 67.1â (1)° and the orientation of the amide N-H and C=O bonds is anti. In the crystal, mol-ecules are linked by N-Hâ¯O and N-Hâ¯S hydrogen bonds.