MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation

• Published in: Circulation (New York, N.Y.) Vol. 127; no. 14; pp. 1466 - 1475
• Main Authors: Dawson, Kristin, Wakili, Reza, Ordög, Balázs, Clauss, Sebastian, Chen, Yu, Iwasaki, Yuki, Voigt, Niels, Qi, Xiao Yan, Sinner, Moritz F, Dobrev, Dobromir, Kääb, Stefan, Nattel, Stanley
• Format: Journal Article
• Language: English
• Published: United States 09.04.2013
• Subjects: Aged; Animals; Atrial Fibrillation - genetics; Atrial Fibrillation - pathology; Atrial Fibrillation - physiopathology; Biomarkers - blood; Disease Models, Animal; Dogs; Female; Fibrosis - genetics; Fibrosis - pathology; Fibrosis - physiopathology; Heart Atria - metabolism; Heart Atria - pathology; Heart Atria - physiopathology; Heart Failure - genetics; Heart Failure - pathology; Heart Failure - physiopathology; Humans; Male; Mice; Mice, Inbred C57BL; MicroRNAs - blood; MicroRNAs - genetics; Middle Aged; Myocardium - metabolism; Myocardium - pathology; Pacemaker, Artificial; Ventricular Remodeling - genetics; Ventricular Remodeling - physiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.112.001207

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. 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. MiR29 likely plays a role in atrial fibrotic remodeling and may have value as a biomarker and/or therapeutic target.