Cardioprotection by acetylcholine: a novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway.

Abstract

Mitochondrial biogenesis disorders appear to play an essential role in cardiac dysfunction. Acetylcholine as a potential pharmacologic agent exerts cardioprotective effects. However, its direct action on mitochondria biogenesis in acute cardiac damage due to ischemia/reperfusion remains unclear. The present study determined the involvement of mitochondrial biogenesis and function in the cardiopotection of acetylcholine in H9c2 cells subjected to hypoxia/reoxygenation (H/R). Our findings demonstrated that acetylcholine treatment on the beginning of reoxygenation improved cell viability in a concentration-dependent way. Consequently, acetylcholine inhibited the mitochondrial morphological abnormalities and caused a significant increase in mitochondrial density, mass, and mitochondrial DNA (mtDNA) copy number. Accordingly, acetylcholine enhanced ATP synthesis, membrane potentials, and activities of mitochondrial complexes in contrast to H/R alone. Furthermore, acetylcholine stimulated the transcriptional activation and protein expression of peroxisome proliferator-activated receptor co-activator 1 alpha (PGC-1α, the central factor for mitochondrial biogenesis) and its downstream targets including nuclear respiration factors and mitochondrial transcription factor A. In addition, acetylcholine activated phosphorylation of AMP-activated protein kinase (AMPK), which was located upstream of PGC-1α. Atropine (muscarinic receptor antagonist) abolished the favorable effects of acetylcholine on mitochondria. Knockdown of PGC-1α or AMPK by siRNA blocked acetylcholine-induced stimulating effects on mtDNA copy number and against cell injury. In conclusion, we suggested, acetylcholine as a mitochondrial nutrient, protected against the deficient mitochondrial biogenesis and function induced by H/R injury in a cellular model through muscarinic receptor-mediated, AMPK/PGC-1α-associated regulatory program, which may be of significance in elucidating a novel mechanism underlying acetylcholine-induced cardioprotection.

• Authors: Lei Sun, Mei Zhao, Xiao-Jiang Yu, Hao Wang, Xi He, Jian-Kang Liu, Wei-Jin Zang
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 228 Issue 6 Pg. 1238-48 (Jun 2013) ISSN: 1097-4652 [Electronic] United States
• PMID: 23139024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• DNA, Mitochondrial
• Multienzyme Complexes
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, rat
• Protective Agents
• RNA, Messenger
• RNA-Binding Proteins
• Transcription Factors
• Adenosine Triphosphate
• AMP-Activated Protein Kinases
• Acetylcholine

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Acetylcholine (pharmacology)
• Adenosine Triphosphate (metabolism)
• Animals
• Cell Line
• Cell Survival (drug effects)
• Cytoprotection
• DNA, Mitochondrial (metabolism)
• Dose-Response Relationship, Drug
• Energy Metabolism (drug effects)
• Gene Expression Regulation
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria, Heart (drug effects, metabolism, ultrastructure)
• Mitochondrial Turnover (drug effects)
• Multienzyme Complexes (metabolism)
• Myocardial Reperfusion Injury (genetics, metabolism, pathology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, ultrastructure)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Phosphorylation
• Protective Agents (pharmacology)
• RNA Interference
• RNA, Messenger (metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Rats
• Signal Transduction (drug effects)
• Transcription Factors (genetics, metabolism)
• Transfection