title: Cardiomyocyte-specific deletion of Gsk3α mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure.
abstract: BACKGROUND
  Injury due to myocardial infarction (MI) is largely irreversible. Once an infarct has occurred, the clinical goal becomes limiting remodeling, preserving left ventricular function, and preventing heart failure. Although traditional approaches (e.g., β-blockers) partially preserve left ventricular function, novel strategies are needed to limit ventricular remodeling post-MI.
  
  
  OBJECTIVE
  The aim of this study was to determine the role of glycogen synthase kinase-3α (GSK-3α) in post-MI remodeling.
  
  
  METHODS
  Mice with cardiomyocyte-specific conditional deletion of Gsk3α and littermate controls underwent sham or MI surgery. Heart function was assessed using serial M-mode echocardiography.
  
  
  RESULTS
  Gsk3α deletion in the heart markedly limits remodeling and preserves left ventricular function post-MI. This is due at least in part to dramatic thinning and expansion of the scar in the control hearts, which was less in the heart of knockout (KO) mice. In contrast, the border zone in the KO mice demonstrated a much thicker scar, and there were more viable cardiomyocytes within the scar/border zone. This was associated with less apoptosis and more proliferation of cardiomyocytes in the KO mice. Mechanistically, reduced apoptosis was due, at least in part, to a marked decrease in the Bax/Bcl-2 ratio, and increased cardiomyocyte proliferation was mediated through cyclin E1 and E2F-1 in the hearts of the KO mice.
  
  
  CONCLUSIONS
  Taken together, these findings show that reducing GSK-3α expression in cardiomyocytes limits ventricular remodeling and preserves cardiac function post-MI. Specifically targeting GSK-3α could be a novel strategy to limit adverse remodeling and heart failure.
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.|Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN,USA.
authors.forename: Firdos
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.|Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN,USA.
authors.forename: Hind
authors.initials: H
authors.lastname: Lal
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jibin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Vagnozzi
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Justine E
authors.initials: JE
authors.lastname: Yu
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Xiying
authors.initials: X
authors.lastname: Shang
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.|Cardiology Division, Temple University School of Medicine, Philadelphia, PA, USA.|Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN,USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D017353:Gene Deletion; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D004247:DNA; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: GSK-3α; cardiomyocyte proliferation; heart failure; myocardial infarction; ventricular remodeling