Conflict of interest: none.
Original Research Article
Cardioprotection by acetylcholine: A novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway†
Version of Record online: 25 FEB 2013
Copyright © 2012 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 228, Issue 6, pages 1238–1248, June 2013
How to Cite
Sun, L., Zhao, M., Yu, X.-J., Wang, H., He, X., Liu, J.-K. and Zang, W.-J. (2013), Cardioprotection by acetylcholine: A novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway. J. Cell. Physiol., 228: 1238–1248. doi: 10.1002/jcp.24277
- Issue online: 25 FEB 2013
- Version of Record online: 25 FEB 2013
- Accepted manuscript online: 8 NOV 2012 09:45AM EST
- Manuscript Accepted: 29 OCT 2012
- Manuscript Received: 4 MAY 2012
- National Natural Science Foundation of China. Grant Numbers: 30930105, 81120108002
- CMB Distinguished Professorships Award. Grant Number: F510000/G16916404
- Natural Science Foundation of the Education Bureau of Shaanxi Province. Grant Number: 2012JZ4001
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. J. Cell. Physiol. 228: 1238–1248, 2013. © 2012 Wiley Periodicals, Inc.