Document Detail


Glycogen synthase kinase-3α limits ischemic injury, cardiac rupture, post-myocardial infarction remodeling and death.
MedLine Citation:
PMID:  22086876     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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.
CONCLUSION: 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:
Hind Lal; Jibin Zhou; Firdos Ahmad; Raihana Zaka; Ronald J Vagnozzi; Morgan Decaul; James Woodgett; Erhe Gao; Thomas Force
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-15
Journal Detail:
Title:  Circulation     Volume:  125     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-04     Completed Date:  2012-02-24     Revised Date:  2012-06-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  65-75     Citation Subset:  AIM; IM    
Affiliation:
Center for Translational Medicine, Thomas Jefferson University, College Building, Rm 316, 1025 Walnut St., Philadelphia, PA 19107, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis Regulatory Proteins / deficiency,  genetics,  physiology
Cardiotonic Agents / metabolism,  therapeutic use
Cells, Cultured
Death
Glycogen Synthase Kinase 3 / deficiency,  genetics,  physiology*
Heart Rupture / enzymology*,  genetics,  mortality
Male
Mice
Mice, Knockout
Myocardial Infarction / enzymology*,  genetics,  mortality
Myocytes, Cardiac / enzymology,  pathology
Ventricular Remodeling / genetics,  physiology*
Grant Support
ID/Acronym/Agency:
HL061688/HL/NHLBI NIH HHS; HL091799/HL/NHLBI NIH HHS; MOP12858//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Cardiotonic Agents; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 2.7.11.26/glycogen synthase kinase 3 alpha

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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