MicroRNA29: A Mechanistic Contributor and Potential Biomarker in Atrial Fibrillation

Abstract

Background—: Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF) maintenance. MicroRNA29 (miR29) targets extracellular matrix proteins. In the present study, we examined miR29b changes in patients with AF and/or CHF and in a CHF-related AF animal model and assessed its potential role in controlling atrial fibrous tissue production. Methods and Results—: Control dogs were compared with dogs subjected to ventricular tachypacing for 24 hours, 1 week, or 2 weeks to induce CHF. Atrial miR29b expression decreased within 24 hours in both whole atrial tissue and atrial fibroblasts (−87% and −92% versus control, respectively; p <0.001 for both) and remained decreased throughout the time course. Expression of miR29b extracellular matrix target genes collagen-1A1 (COL1A1), collagen-3A1 (COL3A1), and fibrillin increased significantly in CHF fibroblasts. Lentivirus-mediated miR29b knockdown in canine atrial fibroblasts (−68%; p <0.01) enhanced COL1A1, COL3A1, and fibrillin mRNA expression by 28% ( p <0.01), 19% ( p <0.05), and 20% ( p <0.05), respectively, versus empty virus–infected fibroblasts and increased COL1A1 protein expression by 90% ( p <0.05). In contrast, 3-fold overexpression of miR29b decreased COL1A1, COL3A1, and fibrillin mRNA by 65%, 62%, and 61% (all p <0.001), respectively, versus scrambled control and decreased COL1A1 protein by 60% ( p <0.05). MiR29b plasma levels were decreased in patients with CHF or AF (by 53% and 54%, respectively; both p <0.001) and were further decreased in patients with both AF and CHF (by 84%; p <0.001). MiR29b expression was also reduced in the atria of chronic AF patients (by 54% versus sinus rhythm; p <0.05). Adenoassociated viral–mediated knockdown of miR29b in mice significantly increased atrial COL1A1 mRNA expression and cardiac tissue collagen content. Conclusions—: MiR29 likely plays a role in atrial fibrotic remodeling and may have value as a biomarker and/or therapeutic target.