Overexpression of microRNA-1 Causes Atrioventricular Block in Rodents

摘要

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,I-L) and inward rectifier K+ current (I-K1). Expression of connexin 43 (Cx43) protein was determined by western blot analysis. Alternations of [Ca2+](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,I-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 [Ca2+](i) in ventricular myocytes but a prominent increase of the resting [Ca2+](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.