Journal Article

MicroRNA-221 Is Cardioprotective and Anti-fibrotic in a Rat Model of Myocardial Infarction

Wang, Peipei, Zhou, Yue, Richards, Arthur Mark

2019

Overview

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 (MI). Using in vitro hypoxia and reoxygenation (H/R) of H9c2 and rat cardiac fibroblast (cFB) models, we found that 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-smooth muscle actin (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 (intravenous [i.v.], 1 mg/kg). With treatment, miR-221 increased by ∼15-fold in infarct and peri-infarct zones at day 2 post-MI. At days 7 and 30 post-MI, miR-221 reduced infarct size, fibrosis, and α-SMA+ cells in both infarct and remote myocardium. Left ventricle (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 and P53 and inhibition of phosphorylation at Ser46 and direct targeting on Ddit4, respectively. miR-221 enhances cardiomyocyte survival and protects cardiac function post-MI. It enhances cFB survival yet inhibits their activation, thus reducing adverse cardiac fibrosis. [Display omitted]

• Publisher: Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy,Elsevier
• Subject: Actin / Animal models / Apoptosis / Autophagy / Binding sites / Blood pressure / Cardiac function / cardiac remodeling / Cardiomyocytes / cardioprotection / Cardiovascular disease / Cell size / Collagen / Congestive heart failure / Contraction / Coronary artery / Ddit4 / Fibroblasts / Fibrosis / Genes / Heart attacks / Heart failure / Histology / Hypoxia / Intravenous administration / Ischemia / microRNA / microRNA-221 / MicroRNAs / miRNA / Muscle contraction / Myocardial infarction / Myocardium / p-53 / p53 Protein / Phosphorylation / Protein expression / Proteins / Smooth muscle / Studies / Ventricle