RESUMO
MicroRNAs (miRNAs) have been found to act as key regulators in the pathogenesis of myocardial ischemic-reperfusion (I/R) injury. In this study, we explore the role and mechanism of microRNA-202-3p (miR-202-3p) in regulating cardiomyocyte apoptosis, in respective of the TGF-ß1/Smads signaling pathway by targeting the transient receptor potential cation channel, subfamily M, member 6 (TRPM6). The targeting relationship between miR-202-3p and TRPM6 was verified by a dual-luciferase reporter gene assay. Sprague-Dawley rat models of myocardial I/R injury were initially established and treated with different mimics, inhibitors and siRNAs to test the effects of miR-202-3p and TRPM6 on myocardial I/R injury. The levels of inflammatory factors; IL-1ß, IL-6, TNF-α as well as the degree of myocardial fibrosis and cardiomyocyte apoptosis were determined in rats transfected with different plasmids. TRPM6 was found to be the target of miR-202-3p. Up-regulated miR-202-3p or knockdown of TRPM-6 alleviated oxidative stress and inflammatory response, reduced ventricular mass, altered cardiac hemodynamics, suppressed myocardial infarction, attenuated cell apoptosis, and inhibited myocardial fibrosis. MiR-202-3p overexpression activates the TGF-ß1/Smads signaling pathway by negatively regulating TRPM6 expression. Taken together, these findings suggest that miR-202-3p offers protection against ventricular remodeling after myocardial I/R injury via activation of the TGF-ß1/Smads signaling pathway.
Assuntos
MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Proteínas Smad/metabolismo , Canais de Cátion TRPM/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antagomirs/metabolismo , Apoptose , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Superóxido Dismutase/metabolismo , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/genética , Regulação para CimaRESUMO
Cholesterol efflux from macrophage foam cells, the initial step of reverse cholesterol transport, is assumed to be the most relevant step with respect to atherosclerosis. As one of the ATP-binding cassette transporter (ABC) family members, ABCG1 plays a critical role in the process of cholesterol efflux. It has been recently identified to export cellular cholesterol to large HDL particles. For mature HDL constitutes the bulk of the plasma HDL, ABCG1 is responsible for the majority of the cholesterol efflux from macrophage foam cells to serum. Overexpression of ABCG1 improves HDL function through stimulating cholesterol export. Therefore, it could be hypothesized that ABCG1 would be a new target for the treatment of atherosclerosis.
