MicroRNA29: A Mechanistic Contributor and Potential Biomarker in Atrial Fibrillation
Background—Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF)-maintenance. MicroRNA (miR)-29 targets extracellular-matrix (ECM) proteins. Here, we studied 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%***, -92%*** vs. control respectively; ***P<0.001), and remained decreased throughout the time-course. Expression of miR29b ECM 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%**, 19%* (*P<0.05) and 20%* respectively versus empty-virus-infected fibroblasts and increased COL1A1 protein expression by 90%*. In contrast, 3-fold overexpression of miR29b decreased COL1A1, COL3A1 and fibrillin mRNA by 65%***, 62%*** and 61%*** respectively versus scrambled control and COL1A1 protein by 60%*. MiR29b plasma-levels were decreased in patients with CHF or AF (by 53%***, 54%*** respectively) and were further decreased in patients with both AF and CHF (by 84%***). MiR29b-expression was also reduced in the atria of chronic-AF patients (by 54%* vs. sinus rhythm). Adenoasssociated-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 might have value as a biomarker and/or therapeutic target.
- Received January 8, 2013.
- Accepted February 22, 2013.