Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion

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 s...

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Published in:American journal of physiology. Heart and circulatory physiology 2011-06, Vol.300 (6), p.H2261-H2271
Main Authors: Kanamori, Hiromitsu, Takemura, Genzou, Goto, Kazuko, Maruyama, Rumi, Ono, Koh, Nagao, Kazuya, Tsujimoto, Akiko, Ogino, Atsushi, Takeyama, Toshiaki, Kawaguchi, Tomonori, Watanabe, Takatomo, Kawasaki, Masanori, Fujiwara, Takako, Fujiwara, Hisayoshi, Seishima, Mitsuru, Minatoguchi, Shinya
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Animals
Autophagy
Autophagy - drug effects
Autophagy - physiology
Autophagy-Related Protein 5
Cells, Cultured
Coronary Occlusion - complications
Coronary vessels
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Heart attacks
Lysosomal-Associated Membrane Protein 2 - antagonists & inhibitors
Lysosomal-Associated Membrane Protein 2 - metabolism
Macrolides - pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microtubule-Associated Proteins - antagonists & inhibitors
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Models, Animal
Myocardial Infarction - etiology
Myocardial Infarction - metabolism
Myocardial Infarction - physiopathology
Myocardial Ischemia - metabolism
Myocardial Ischemia - physiopathology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
RNA, Small Interfering - pharmacology
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Summary: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.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.01056.2010