Portal de Periódicos da CAPES

Overexpression of M3 Muscarinic Receptor Is a Novel Strategy for Preventing Sudden Cardiac Death in Transgenic Mice

2011; BioMed Central; Volume: 17; Issue: 11-12 Linguagem: Inglês

10.2119/molmed.2011.00093

1528-3658

Yan Liu, Lihua Sun, Zhenwei Pan, Yunlong Bai, Ning Wang, Jinlong Zhao, Chaoqian Xu, Zhi Li, Baoxin Li, Zhimin Du, Yanjie Lu, Xu Gao, Baofeng Yang,

Neuroscience and Neuropharmacology Research

The present study was designed to investigate the cardiac benefits of M3 muscarinic receptor (M3-mAChR) overexpression and whether these effects are related to the regulation of the inward rectifying K+ channel by microRNA-1 (miR-1) in a conditional overexpression mouse model. A cardiac-specific M3-mAChR transgenic mouse model was successfully established for the first time in this study using microinjection, and the overexpression was confirmed by both reverse transcriptase-polymerase chain reaction and Western blot techniques. We demonstrated that M3-mAChR overexpression dramatically reduced the incidence of arrhythmias and decreased the mortality in a mouse model of myocardial ischemia-reperfusion (I/R). By using whole-cell patch techniques, M3-mAChR overexpression significantly shortened the action potential duration and restored the membrane repolarization by increasing the inward rectifying K+ current. By using Western blot techniques, M3-mAChR overexpression also rescued the expression of the inward rectifying K+ channel subunit Kir2.1 after myocardial I/R injury. This result was accompanied by suppression of upregulation miR-1. We conclude that M3-mAChR overexpression reduced the incidence of arrhythmias and mortality after myocardial I/R by protecting the myocardium from ischemia in mice. This effect may be mediated by increasing the inward rectifying K+ current by downregulation of arrhythmogenic miR-1 expression, which might partially be a novel strategy for antiarrhythmias, leading to sudden cardiac death.