Abstract 12545: Potential Role of MicroRNA-29b in Atrial Fibrillation-Promoting Fibrotic Remodeling
Introduction: Heart failure (HF) causes an atrial fibrotic substrate for atrial fibrillation (AF) maintenance, but the underlying mechanisms are incompletely understood. MicroRNA (miR) 29b suppresses collagen production and decreased miR29b expression promotes fibrotic responses. This study assessed the potential contribution of miR29b changes to HF-induced atrial fibrotic remodeling.
Methods: Experiments were performed in a canine HF model of AF and atrial fibrosis induced by ventricular tachypacing (VTP, 240 bpm). We studied 4 groups: 24 h, 1 wk, 2 wk VTP and control (CTL) dogs (n=8/group). Expression of miR29b in left atrial (LA) tissue and of extracellular matrix (ECM) target genes collagen (COL) 1A1, COL3A1 and fibrillin (FIB) in isolated LA fibroblasts (AFBs) was assessed by real time qPCR.
Results: After 1 wk, VTP remodeled atria showed increased AF duration (17-fold***, p<0.001) and fibrosis (4-fold***), which remained elevated at 2 wk VTP (22-fold***, 6-fold *** respectively). MiR29b expression fell rapidly after 24 h VTP (−90%,***) and remained reduced at 1 wk (−75%,** p<0.01) and 2 wk VTP (−61% *, p<0.05), while target gene expression showed a significant increase in COL1A1 (16-fold ***), COL3A1 (8-fold**), and FIB (2.5-fold*) after 2 wk VTP. To assess regulation of miR29b by the HF mediator TGFβ , we examined the effect of 48 h TGFβ treatment (50 ng/ml) on AFB gene expression. TGFβ decreased AFB expression of mir29b (−44%*) and increased AFB expression of COL1A1 (+50%***). To further evaluate the potential role of miR29b in altered AFB ECM gene expression, we studied the effects of lentiviral-mediated miR29b-knockdown and miR29b-overexpression in AFBs. Mir29b-knockdown increased the expression of fibrotic genes COL1A1 (+124%***) and FIB (+30%*), while mir29b-overexpression decreased AFB expression of COL1A1 (−40% *) and COL3A1 (−25%*).
Conclusions: VTP-induced HF causes a rapid and sustained decrease in miR29b expression, which is followed by increased expression of fibrosis-related miR29b-target ECM genes. TGFβ induces miR29b downregulation in AFBs. In vitro knockdown of miR29b mimics in vivo changes, suggesting a causal role of mir29b downregulation in CHF-related generation of atrial fibrosis via TGFβ signaling.
- © 2010 by American Heart Association, Inc.