Over-expression of microRNA-145 drives alterations in β-adrenergic signaling and attenuates cardiac remodeling in heart failure post myocardial infarction.

Background: 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 beta-adrenergic signaling and cardiac remodeling in heart failure (HF) remains unclarified. Methods and Results: 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 beta-adrenergic receptor (beta AR) stimulation was reduced. Furthermore, miR-145 increased 1-type calcium current (I-ca) density while decreased I-ca response to beta-adrenergic stimulation with isoproterenol. The alterations in BAR signaling might be predominant due to miR-145-mediated activation of Akt/CREB cascades. At high frequency pacing, Ca2+ transient, cell shortening and frequency of Ca2+ waves were significantly improved in AD-miR-145 group. Western blotting revealed that increased expression of Ca(v)1.2, Ca2+-ATPase, beta 2AR, GNAI3 and decreased level of CaMKII might be attributed to the cardioprotective effects of miR-145. Conclusion: miR-145 effectively alleviates HF-related cardiac remodeling by improving cardiac dilation, fibrosis, intracellular Ca2+ mishandling and electrophysiological instability.