Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction 
of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein 
connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy 
leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether 
miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. 
Thus, in this study we investigated whether a reduction in the extent of cardiac 
hypertrophy could limit the pathological electrical remodeling of Cx43 and the 
onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical 
constriction of the ascending aorta to induce pathologic left ventricular 
hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg 
valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 
weeks. Sham surgery was performed for control groups. Programmed ventricular 
stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When 
compared to sham controls, rats from LVH group showed a significant decrease of 
miR-1 and an increase of Cx43 expression and its ERK1/2-dependent 
phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL 
administration to rats with aortic banding significantly reduced cardiac 
hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and 
phosphorylation. Gain- and loss-of-function experiments in neonatal 
cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. 
Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and 
increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. 
Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector 
intra-myocardial injection reduced Cx43 expression and phosphorylation in mice 
with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression 
and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of 
pressure overload-induced myocyte hypertrophy reduces the risk of 
life-threatening VT by normalizing miR-1 expression levels with the consequent 
stabilization of Cx43 expression and activity within the gap junction.