MicroRNA-221 is cardioprotective and anti-fibrotic in a rat model of myocardial infarction

Abstract Reduced myocardial miR-221 expression is associated with severe cardiac fibrosis in heart failure patients. We aimed to demonstrate its mechanisms in cardioprotection and remodeling following myocardial infarction. Using in vitro hypoxia/reperfusion (H/R) of H9c2 and rat cardiac fibroblast (cFB) models, miR-221 protects H9c2 through combined anti-apoptotic and anti-autophagic effects and cFB via anti-autophagic effects alone in H/R. It inhibits myofibroblast (myoFB) activation as indicated by lowering α-SMA expression, gel contraction and collagen synthesis (Sircol assay). In vivo, following left coronary artery ligation (MI), rats were treated with miR-221 mimics (i.v. 1mg/kg). With treatment, miR-221 increased by ∼15-fold in infarct and peri-infarct zones at day-2 post-MI. At day-7 and -30 post-MI, miR-221 reduced infarct size, fibrosis and α-SMA + cells in both infarct and remote myocardium. Left ventricular (LV) function was preserved as indicated by ejection fraction, infarct thickness, LV developed pressure, +/-dP/dt and end diastolic pressure. We demonstrated the anti-apoptotic and anti-autophagic effects were due to combined mechanisms of direct targeting on Bak1, p53 and inhibition of phosphorylation at Ser46 and direct targeting on Ddit4 respectively. Conclusions miR-221 enhances cardiomyocyte survival and protects cardiac function post-MI. It enhances cFB survival yet inhibits their activation thus reducing adverse cardiac fibrosis.