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

Abstract

The present study was designed to investigate the cardiac benefits of M 3 muscarinic receptor (M 3 -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 M 3 -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 M 3 -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, M 3 -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, M 3 -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 M 3 -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.

Arrhythmogenesis Toxicity of Aconitine Is Related to Intracellular Ca2+ Signals

“…Ventricular myocytes were isolated by an enzymatic dissociation method similar to that described previously 19,20. Rats were anaesthetized with pentobarbital by peritoneal injection.…”

Novel strategies and underlying protective mechanisms of modulation of vagal activity in cardiovascular diseases

“…Pharmacological activation of M 3 receptors by choline was cardioprotective in ischaemia‐induced arrhythmias and I/R injury (Zhao et al ., ; Wang et al ., ). Furthermore, overexpression of M 3 receptors decreased the incidence of arrhythmias in a mouse myocardial I/R injury model (Liu et al ., ,). In addition, M 3 receptors mediated the vasorelaxation of most blood vessels induced by ACh (Lamping et al ., ; Beny et al ., ; Gericke et al ., ).…”

Mechanisms underlying the autonomic modulation of ventricular fibrillation initiation—tentative prophylactic properties of vagus nerve stimulation on malignant arrhythmias in heart failure

“…Pharmacological activation of M 3 receptors reduces the occurrence of ischaemia-, aconitine- and ouabain-induced ventricular arrhythmias [107]. Further to this, over-expression of the M 3 mAChR gene reduces the occurrence of spontaneous arrhythmias in a mouse model of ischaemia reperfusion [108]. The role of the M 3 receptor in regulating cardiac repolarisation and cell-to-cell communication is particularly relevant to the discussion of ventricular arrhythmia susceptibility.…”