title: Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non-hypoxic induction of HIF-1alpha.
abstract: Electrical stimulation of the vagal efferent nerve improves the survival of myocardial infarcted rats. However, the mechanism for this beneficial effect is unclear. We investigated the effect of acetylcholine (ACh) on hypoxia-inducible factor (HIF)-1alpha using rat cardiomyocytes under normoxia and hypoxia. ACh posttranslationally regulated HIF-1alpha and increased its protein level under normoxia. ACh increased Akt phosphorylation, and wortmannin or atropine blocked this effect. Hypoxia-induced caspase-3 activation and mitochondrial membrane potential collapse were prevented by ACh. Dominant-negative HIF-1alpha inhibited the cell protective effect of ACh. In acute myocardial ischemia, vagal nerve stimulation increased HIF-1alpha expression and reduced the infarct size. These results suggest that ACh and vagal stimulation protect cardiomyocytes through the PI3K/Akt/HIF-1alpha pathway.
authors.affiliation: Department of Cardiovascular Control, Kochi Medical School, Nankoku 783-8505, Japan. kakinuma@med.kochi-u.ac.jp
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kakinuma
authors.forename: Motonori
authors.initials: M
authors.lastname: Ando
authors.forename: Masanori
authors.initials: M
authors.lastname: Kuwabara
authors.forename: Rajesh G
authors.initials: RG
authors.lastname: Katare
authors.forename: Koji
authors.initials: K
authors.lastname: Okudela
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sato
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D000860:Hypoxia / Q000503:physiopathology / Q000517:prevention & control*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis*; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D000109:Acetylcholine