miR-146a抑制NF-κB通路上调KChIP2改善心肌肥厚的机制研究

Cardiac hypertrophy is a common myocardial remodeling performance and cause the disorder of cardiomyocytes electrophysiological activity and calcium homeostasis imbalance, which is significantly increase the risk of myocardial infarction, arrhythmia, heart failure, sudden cardiac death, but the mechanism of cardiac hypertrophy is not clear. miR-146a is a highly conservative endogenous non-code protein microRNA. It has shown that it could attenuate the inflammatory reaction and improve myocardial ischemia and atherosclerosis by inhibit the NF-κB pathway .K+ channel interaction protein 2 (KChIP2) is involved in the formation of repolarization current and calcium homeostasis in myocyte and down-regulated by NF-κB. It has been found the up-regulation of KChIP2 can improve cardiac hypertrophy induced by transverse aortic constriction(TAC). We found a significantly reduction of miR146a and KChIP2 expression in cardiac hypertrophy induced by TAC in mice, moreover, higher miR146a expression could reduce the cell hypertrophy related genes such as ANP and β-MHC. Therefore, the mice cardiac hypertrophy model induced by TAC will be used to explored the exact mechanisms of miR146a improve the myocardial hypertrophy in this study, which may be provided the theoretical basis and strategy to protect it from cardiac hypertrophy.

心肌肥厚是临床上常见的心肌重构表现，可导致心肌细胞电活动紊乱和钙稳态失调，显著增加心肌梗死、心力衰竭、心脏性猝死风险，但其机制并不明确。miR146a是一类内源性非编码蛋白的高度保守的microRNA，其可通过下调NF-κB抑制炎症改善心肌缺血及动脉粥样硬化，但其在心肌肥厚中的作用并不清楚。钾离子通道相互作用蛋白2（KChIP2）是一种参与心肌细胞复极化电流形成和钙稳态调节的蛋白分子，接受NF-κB负调控，既往研究显示上调KChIP2可改善心肌肥厚。我们前期实验在跨主动脉缩窄（TAC）致心肌肥厚实验中发现miR146a和KChIP2表达显著下调，且上调miR146a可下调AngII刺激后心肌细胞肥大相关基因ANP和β-MHC。本研究拟使用TAC小鼠心肌肥厚模型，通过腺病毒技术上调miR146a，明确miR146a改善心肌肥厚的具体作用机制，为心肌肥厚的防治提供新的思路和理论依据。

心肌肥厚是临床上常见的心脏病理改变，可导致心肌细胞电活动紊乱和钙稳态失调，显著增加心力衰竭、心脏性猝死风险。miR146a是一类内源性非编码蛋白的高度保守的microRNA。其可通过下调NF-κB抑制炎症改善心肌缺血及动脉粥样硬化，但其在心肌肥厚中的作用并不清楚。钾离子通道相互作用蛋白2（KChIP2）是一种参与心肌细胞复极化电流形成和钙稳态调节的蛋白分子，接受NF-κB负调控，既往研究显示上调KChIP2可改善心肌肥厚。因此我们前期实验在跨主动脉狭窄（TAC）致心肌肥厚实验中发现miR146a和KChIP2表达显著下调，且上调miR146a可下调AngII刺激后心肌细胞肥大相关基因ANP和β-MHC。.本项目采用TAC术式制作心肌肥厚动物模型，AngII刺激原代心肌细胞后制作心肌细胞肥大模型进行研究。体内和体外实验均发现心肌细胞肥大后可引起miR146a和KChIP2表达下调，且激活NF-κB通路和引发心肌细胞钙稳态失衡。通过构建过表达miR146a和KChIP2的AAV-9腺病毒，构建体内和体外miR146a和KChIP2过表达的动物和细胞模型，结果发现均可改善心肌肥厚。本研究结果为心肌肥厚的发生发展提供了新的机制，也为心肌肥厚的防治初步的治疗线索和理论依据。