Choline produces cytoprotective effects against ischemic myocardial injuries: evidence for the role of cardiac m3 subtype muscarinic acetylcholine receptors.
OBJECTIVE
Accumulating evidence indicates the presence of functional M3 subtype of acetylcholine muscarinic receptors (M(3)-mAChR), in addition to the well-recognized M(2)-mAChR, in the heart of various species including man. However, the pathophysiological role of the cardiac M(3)-mAChR remain undefined. This study was designed to explore the possible role of M(3)-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 M(3)-selective antagonists but not by the M(2)-selective antagonist. Choline/M(3)-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.


CONCLUSIONS
Choline improves cardiac function and reduces ischemic myocardial injuries via stimulating the cardiac M(3)-mAChRs which in turn result in alterations of multiple signaling pathways leading to cytoprotection. The findings suggest M(3)-mAChR as a new target for drug development for improving cardiac function and preventing cardiac injuries during ischemia/reperfusion.
Yang
Baofeng
B
Department of Pharmacology, State-Province Key Laboratory, Harbin Medical University, Harbin, Canada.
Lin
Huixian
H
Xu
Chaoqian
C
Liu
Yan
Y
Wang
Huizhen
H
Han
Hong
H
Wang
Zhiguo
Z
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002794:Choline / Q000627:therapeutic use*; D003327:Coronary Disease / Q000503:physiopathology; D019610:Cytoprotection; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013482:Superoxide Dismutase / Q000097:blood
D043587:Receptor, Muscarinic M3; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D002794:Choline; D002118:Calcium