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 β-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 β-adrenergic receptor (βAR) stimulation was reduced. Furthermore, miR-145 increased L-type calcium current (I_Ca) density while decreased I_Ca 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, 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_v1.2, Ca²⁺-ATPase, β2AR, 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.

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