Abstract 12548: MicroRNA-1 Downregulation Modulates Gap Junction Levels of Expression and Induces Ventricular Tachyarrhythmias in Rat Hypertrophied Hearts
During left ventricular hypertrophy (LVH), gap junctions and connexin 43 (Cx43) dysfunction cause an important electrical disarray leading to ventricular tachyarrhythmias (VT). The role of microRNA in VT has not been fully elucidated. Therefore, the aim of this study was to investigate whether valsartan (VAL) could limit the electrical remodeling and the onset of VT by modulating miR-1 and Cx43 expression. Twenty Wistar male rats (90-120 g weight) were randomly assigned to receive either 10 mg/kg VAL or placebo for 12 weeks after ascending aorta constriction (BAN+VAL, n= 12; BAN, n= 8). Additional rats were used as sham (SHAM+VAL, n= 10; SHAM, n= 10). Serial echocardiographic assessments were performed, together with hemodynamic measurements and electrophysiological studies (EPS) at the end of the protocol. LVs were harvested and snap frozen for immunoblotting analysis and real time quantitative RT-PCR. VAL significantly reduced LV echocardiographic mass 12 weeks after banding. EPS conducted with standard protocol (100 ms basal cycle length followed by three extrastimuli) determined an increased susceptibility to VT in BAN group as indicated by induction of fibrillation and torsade de pointes compared to BAN+VAL in which only premature ventricular contractions were induced. Hemodynamic measurements showed lower LV end-diastolic pressures and a significant blood pressure profile improvement in BAN+VAL group compared to BAN rats. RT-PCR showed a significant decrease of miR-1 levels in BAN rats, compared to SHAM rats (2.3 fold decrease, p<0,03), which was related to significantly increased levels of Cx43 (3 fold increase, p<0,03). Interestingly, VAL in banded rats prevented miR-1 down-regulation (1.7 fold increase, p<0,03) and Cx-43 up-regulation (1,3 fold decrease, p<0,03), therefore leading to a dramatic reduction of VT. Finally, immunoblotting analysis displayed increased phosphorylation of Cx43 on ser368 after banding, which was markedly prevented by VAL (1,9 fold decrease, p<0.001). Angiotensin receptor antagonization diminished LVH and improved cardiac function 12 weeks after aortic banding. VAL significantly prevented miR-1 down-regulation and Cx-43 remodulation after pressure overload, hence decreasing susceptibility to VT.
- © 2011 by American Heart Association, Inc.