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Cardioprotection by acetylcholine: a novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway.
J Cell Physiol. 2013 Jun; 228(6):1238-48.JC

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+Show Affiliations

Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23139024

Citation

Sun, Lei, et al. "Cardioprotection By Acetylcholine: a Novel Mechanism Via Mitochondrial Biogenesis and Function Involving the PGC-1α Pathway." Journal of Cellular Physiology, vol. 228, no. 6, 2013, pp. 1238-48.
Sun L, Zhao M, Yu XJ, et al. Cardioprotection by acetylcholine: a novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway. J Cell Physiol. 2013;228(6):1238-48.
Sun, L., Zhao, M., Yu, X. J., Wang, H., He, X., Liu, J. K., & Zang, W. J. (2013). Cardioprotection by acetylcholine: a novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway. Journal of Cellular Physiology, 228(6), 1238-48. https://doi.org/10.1002/jcp.24277
Sun L, et al. Cardioprotection By Acetylcholine: a Novel Mechanism Via Mitochondrial Biogenesis and Function Involving the PGC-1α Pathway. J Cell Physiol. 2013;228(6):1238-48. PubMed PMID: 23139024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardioprotection by acetylcholine: a novel mechanism via mitochondrial biogenesis and function involving the PGC-1α pathway. AU - Sun,Lei, AU - Zhao,Mei, AU - Yu,Xiao-Jiang, AU - Wang,Hao, AU - He,Xi, AU - Liu,Jian-Kang, AU - Zang,Wei-Jin, PY - 2012/05/04/received PY - 2012/10/29/accepted PY - 2012/11/10/entrez PY - 2012/11/10/pubmed PY - 2013/4/20/medline SP - 1238 EP - 48 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 228 IS - 6 N2 - 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. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/23139024/Cardioprotection_by_acetylcholine:_a_novel_mechanism_via_mitochondrial_biogenesis_and_function_involving_the_PGC_1α_pathway_ L2 - https://doi.org/10.1002/jcp.24277 DB - PRIME DP - Unbound Medicine ER -