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

Lei Sun1, Mei Zhao, Xiao-Jiang Yu

  • 1Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.

Insights

Acetylcholine protects heart cells from damage by improving mitochondrial biogenesis and function. This occurs via muscarinic receptors and the AMPK/PGC-1α pathway, offering a novel cardioprotection mechanism.

Area of Science:

  • Cardiovascular Research
  • Mitochondrial Biology
  • Pharmacology

Background:

  • Mitochondrial dysfunction is key in cardiac damage.
  • Acetylcholine offers cardioprotection, but its mitochondrial effects are unclear.
  • Acute cardiac injury involves ischemia/reperfusion (I/R).

Purpose of the Study:

  • To investigate acetylcholine's role in mitochondrial biogenesis and function during hypoxia/reoxygenation (H/R) induced cardiac injury.
  • To elucidate the underlying molecular mechanisms of acetylcholine's cardioprotective effects.

Main Methods:

  • H9c2 cells were subjected to H/R.
  • Acetylcholine treatment was administered at reoxygenation.
  • Mitochondrial function, biogenesis markers (mtDNA, PGC-1α, AMPK), and cell viability were assessed.
  • Muscarinic receptor antagonist (atropine) and siRNA knockdown (PGC-1α, AMPK) were used.

Main Results:

  • Acetylcholine improved cell viability and mitochondrial morphology in an H/R model.
  • It increased mitochondrial density, mass, mtDNA copy number, ATP synthesis, and membrane potential.
  • Acetylcholine upregulated PGC-1α and its downstream targets, and activated AMPK phosphorylation.
  • These effects were blocked by atropine and siRNA knockdown of PGC-1α or AMPK.

Conclusions:

  • Acetylcholine protects against H/R-induced mitochondrial dysfunction and injury.
  • This protection involves muscarinic receptor-mediated activation of the AMPK/PGC-1α pathway.
  • Acetylcholine acts as a mitochondrial nutrient, revealing a novel cardioprotection mechanism.

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