title: Glycogen synthase kinase-3α limits ischemic injury, cardiac rupture, post-myocardial infarction remodeling and death.
abstract: BACKGROUND
  The molecular pathways that regulate the extent of ischemic injury and post-myocardial infarction (MI) remodeling are not well understood. We recently demonstrated that glycogen synthase kinase-3α (GSK-3α) is critical to the heart's response to pressure overload. However, the role, if any, of GSK-3α in regulating ischemic injury and its consequences is not known.
  
  
  RESULTS
  MI was induced in wild-type (WT) versus GSK-3α((-/-)) (KO) littermates by left anterior descending coronary artery ligation. Pre-MI, WT, and KO hearts had comparable chamber dimensions and ventricular function, but as early as 1 week post-MI, KO mice had significantly more left ventricular dilatation and dysfunction than WT mice. KO mice also had increased mortality during the first 10 days post-MI (43% versus 22%; P=0.04), and postmortem examination confirmed cardiac rupture as the cause of most of the deaths. In the mice that survived the first 10 days, left ventricular dilatation and dysfunction remained worse in the KO mice throughout the study (8 weeks). Hypertrophy, fibrosis, and heart failure were all increased in the KO mice. Given the early deaths due to rupture and the significant reduction in left ventricular function evident as early as 1 week post-MI, we examined infarct size following a 48-hour coronary artery ligation and found it to be increased in the KO mice. This was accompanied by increased apoptosis in the border zone of the MI. This increased susceptibility to ischemic injury-induced apoptosis was also seen in cardiomyocytes isolated from the KO mice that were exposed to hypoxia. Finally, Bax translocation to the mitochondria and cytochrome C release into the cytosol were increased in the KO mice.
  
  
  CONCLUSIONS
  GSK-3α confers resistance to ischemic injury, at least in part, via limiting apoptosis. Loss of GSK-3α promotes ischemic injury, increases risk of cardiac rupture, accentuates post-MI remodeling and left ventricular dysfunction, and increases the progression to heart failure. These findings are in striking contrast to multiple previous reports in which deletion or inhibition of GSK-3β is protective.
authors.affiliation: Center for Translational Medicine, Thomas Jefferson University, College Building, Rm 316, 1025 Walnut St., Philadelphia, PA 19107, USA.
authors.forename: Hind
authors.initials: H
authors.lastname: Lal
authors.forename: Jibin
authors.initials: J
authors.lastname: Zhou
authors.forename: Firdos
authors.initials: F
authors.lastname: Ahmad
authors.forename: Raihana
authors.initials: R
authors.lastname: Zaka
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Vagnozzi
authors.forename: Morgan
authors.initials: M
authors.lastname: Decaul
authors.forename: James
authors.initials: J
authors.lastname: Woodgett
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002316:Cardiotonic Agents / Q000378:metabolism / Q000627:therapeutic use; D002478:Cells, Cultured; D003643:Death; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006341:Heart Rupture / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
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