Overexpression of microRNA-1 Causes Atrioventricular Block in Rodents

The present study was designed to investigate whether microRNAs (miRNAs) are involved in atrioventricular block (AVB) in the setting of myocardial ischemia (MI). A cardiac-specific miR-1 transgenic (Tg) mouse model was successfully established for the first time in this study using microinjection. miR-1 level was measured by real-time qRT-PCR. Whole-cell patch clamp was employed to record L-type calcium current (I(Ca,L)) and inward rectifier K(+) current (I(K1)). Expression of connexin 43 (Cx43) protein was determined by western blot analysis. Alternations of [Ca(2+)](i )was detected by laser scanning confocal microscopy in ventricular myocytes. The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. The normalized peak current amplitude of I(Ca,L) was lower in ventricular myocytes from miR-1 Tg mice as compared with WT mice. Similarly, the current density of I(K1) was decreased in miR-1 Tg mice than that in WT mice. Compared with WT mice, miR-1 Tg mice exhibited a significant decrease of the systolic [Ca(2+)](i )in ventricular myocytes but a prominent increase of the resting [Ca(2+)](i). Moreover, Cx43 protein was downregulated in miR-1 Tg mice compared to that in WT mice. Administration of LNA-modified antimiR-1 reversed all the above changes. miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias.