Choline Produces Cytoprotective Effects Against Ischemic Myocardial Injuries: Evidence for the Role of Cardiac M3 Subtype Muscarinic Acetylcholine Receptors

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Abstract
Background/Aims: Accumulating evidence indicates the presence of functional M3 subtype of acetylcholine muscarinic receptors (M3-mAChR), in addition to the well-recognized M2-mAChR, in the heart of various species including man. However, the pathophysiological role of the cardiac M3-mAChR remain undefined. This study was designed to explore the possible role of M3-mAChR in cytoprotection of myocardial infarction and several related signaling pathways as potential mechanisms. Methods: Studies were performed in a rat model of myocardial infarction and in isolated myocytes. Results: We found that choline relieved myocardial injuries during ischemia or under oxidative stress, which was achieved by correcting hemodynamic impairment, diminishing ventricular arrhythmias and protecting cardiomyocytes from apoptotic death. The beneficial effects of choline were reversed by the M3-selective antagonists but not by the M2-selective antagonist. Choline/M3-mAChR activated several survival signaling molecules (antiapoptotic proteins Bcl-2 and ERKs), increased endogenous antioxidant reserve (SOD), and reduced apoptotic mediators (proapoptotic proteins Fas and p38 MAPK) and intracellular Ca2+ overload. Conclusion: Choline improves cardiac function and reduces ischemic myocardial injuries via stimulating the cardiac M3-mAChRs which in turn result in alterations of multiple signaling pathways leading to cytoprotection. The findings suggest M3-mAChR as a new target for drug development for improving cardiac function and preventing cardiac injuries during ischemia/reperfusion.