title: Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion.
abstract: Ischemia is known to potently stimulate autophagy in the heart, which may contribute to cardiomyocyte survival. In vitro, transfection with small interfering RNAs targeting Atg5 or Lamp-2 (an autophagy-related gene necessary, respectively, for the initiation and digestion step of autophagy), which specifically inhibited autophagy, diminished survival among cultured cardiomyocytes subjected to anoxia and significantly reduced their ATP content, confirming an autophagy-mediated protective effect against anoxia. We next examined the dynamics of cardiomyocyte autophagy and the effects of manipulating autophagy during acute myocardial infarction in vivo. Myocardial infarction was induced by permanent ligation of the left coronary artery in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice in which GFP-LC3 aggregates to be visible in the cytoplasm when autophagy is activated. Autophagy was rapidly (within 30 min after coronary ligation) activated in cardiomyocytes, and autophagic activity was particularly strong in salvaged cardiomyocytes bordering the infarcted area. Treatment with bafilomycin A1, an autophagy inhibitor, significantly increased infarct size (31% expansion) 24 h postinfarction. Interestingly, acute infarct size was significantly reduced (23% reduction) in starved mice showing prominent autophagy before infarction. Treatment with bafilomycin A1 reduced postinfarction myocardial ATP content, whereas starvation increased myocardial levels of amino acids and ATP, and the combined effects of bafilomycin A1 and starvation on acute infarct size offset one another. The present findings suggest that autophagy is an innate and potent process that protects cardiomyocytes from ischemic death during acute myocardial infarction.
authors.affiliation: Dept. of Cardiology, Gifu Univ. Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Koh
authors.initials: K
authors.lastname: Ono
authors.forename: Kazuya
authors.initials: K
authors.lastname: Nagao
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsujimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takeyama
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Takatomo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D002478:Cells, Cultured; D054059:Coronary Occlusion / Q000150:complications*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D009203:Myocardial Infarction / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D052119:Lysosomal-Associated Membrane Protein 2; D018942:Macrolides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C040929:bafilomycin A1