title: The role of autophagy emerging in postinfarction cardiac remodelling.
abstract: OBJECTIVE
  Autophagy is activated in cardiomyocytes in ischaemic heart disease, but its dynamics and functional roles remain unclear after myocardial infarction. We observed the dynamics of cardiomyocyte autophagy and examined its role during postinfarction cardiac remodelling.
  
  
  RESULTS
  Myocardial infarction was induced in mice by ligating the left coronary artery. During both the subacute and chronic stages (1 and 3 weeks postinfarction, respectively), autophagy was found to be activated in surviving cardiomyocytes, as demonstrated by the up-regulated expression of microtubule-associated protein-1 light chain 3-II (LC3-II), p62 and cathepsin D, and by electron microscopic findings. Activation of autophagy, specifically the digestion step, was prominent in cardiomyocytes 1 week postinfarction, especially in those bordering the infarct area, while the formation of autophagosomes was prominent 3 weeks postinfarction. Bafilomycin A1 (an autophagy inhibitor) significantly aggravated postinfarction cardiac dysfunction and remodelling. Cardiac hypertrophy was exacerbated in this group and was accompanied by augmented ventricular expression of atrial natriuretic peptide. In these hearts, autophagic findings (i.e. expression of LC3-II and the presence of autophagosomes) were diminished, and activation of AMP-activated protein kinase was enhanced. Treatment with rapamycin (an autophagy enhancer) brought about opposite outcomes, including mitigation of cardiac dysfunction and adverse remodelling. A combined treatment with bafilomycin A1 and rapamycin offset each effect on cardiomyocyte autophagy and cardiac remodelling in the postinfarction heart.
  
  
  CONCLUSIONS
  These findings suggest that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodelling, implying that augmenting autophagy could be a therapeutic strategy.
authors.affiliation: Department of Cardiology, Gifu University 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: 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: 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: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002402:Cathepsin D / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D018942:Macrolides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009320:Atrial Natriuretic Factor; C040929:bafilomycin A1; D055372:AMP-Activated Protein Kinases; D002402:Cathepsin D; C533923:Ctsd protein, mouse; D020123:Sirolimus