Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, PR China.
Cardiovascular Research Institute, Wuhan University, Wuhan, PR China.
Aging (Albany NY). 2020 Jun 18;12(12):11603-11622. doi: 10.18632/aging.103320.
Numerous studies have highlighted the crucial role of microRNA-145 (miR-145) in coronary atherosclerosis and myocardial ischemia reperfusion injury. However, effects of miR-145 on β-adrenergic signaling and cardiac remodeling in heart failure (HF) remains unclarified.
We established HF model in rats with left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD ligation, rats showed substantial aggravation of cardiac dilation and electrophysiological instability. Up-regulation of miR-145 ameliorated HF-induced myocardial fibrosis and prolonged action potential duration. Echocardiography revealed increased basal contractility and decreased left ventricular inner-diameter in miR-145 over-expressed heart, while cardiac response to β-adrenergic receptor (βAR) stimulation was reduced. Furthermore, miR-145 increased L-type calcium current (I) density while decreased I response to β-adrenergic stimulation with isoproterenol. The alterations in βAR signaling might be predominant due to miR-145-mediated activation of Akt/CREB cascades. At high frequency pacing, Ca transient, cell shortening and frequency of Ca waves were significantly improved in AD-miR-145 group. Western blotting revealed that increased expression of Ca1.2, Ca-ATPase, β2AR, GNAI3 and decreased level of CaMKII might be attributed to the cardioprotective effects of miR-145.
miR-145 effectively alleviates HF-related cardiac remodeling by improving cardiac dilation, fibrosis, intracellular Ca mishandling and electrophysiological instability.
许多研究强调了 microRNA-145（miR-145）在冠状动脉粥样硬化和心肌缺血再灌注损伤中的关键作用。然而，miR-145 对心力衰竭（HF）中β-肾上腺素能信号和心脏重构的影响仍不清楚。
我们通过左前降支冠状动脉（LAD）结扎建立了大鼠 HF 模型。LAD 结扎 4 周后，大鼠出现明显的心脏扩张和电生理不稳定加重。miR-145 的上调改善了 HF 诱导的心肌纤维化和动作电位时程延长。超声心动图显示，miR-145 过表达心脏的基础收缩力增加，左心室内径减小，而心脏对β-肾上腺素能受体（βAR）刺激的反应降低。此外，miR-145 增加 L 型钙电流（I）密度，同时降低异丙肾上腺素对βAR 刺激的 I 反应。βAR 信号的改变可能主要是由于 miR-145 介导的 Akt/CREB 级联的激活。在高频起搏时，AD-miR-145 组的钙瞬变、细胞缩短和钙波频率均显著改善。Western blot 显示，增加的 Ca1.2、Ca-ATPase、β2AR、GNAI3 表达和降低的 CaMKII 水平可能归因于 miR-145 的心脏保护作用。
miR-145 通过改善心脏扩张、纤维化、细胞内钙处理和电生理不稳定，有效缓解 HF 相关的心脏重构。
