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Pharmacologic inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) promotes infarct resorption and prevents adverse cardiac remodeling after myocardial infarction in mice.
MedLine Citation:
PMID:  20881611     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
BACKGROUND: Phosphoinositide 3-kinase gamma is upregulated in the heart during acute myocardial infarction (AMI) potentially contributing to the development and maintenance of heart failure.
METHODS: CD-1 male mice were randomly assigned to pharmacologic inhibition of phosphoinositide 3-kinase gamma using AS-605240 (10 mg/kg/day intraperitoneally) or vehicle (NaCl 0.9% + DMSO 25% solution) for 14 days after experimental AMI induced by surgical coronary artery ligation. Echocardiography was performed at baseline and 1, 7, 14, and 28 days after surgery to measure left ventricular dimensions and function. Infarct size was also measured at weekly intervals to evaluate for infarct resorption.
RESULTS: When compared with vehicle-treated mice over the 4-week period, animals treated with AS-605240 showed a smaller increase in left ventricular cavitary dimensions, a smaller decrease in left ventricular systolic function (P < 0.05), and a significant increase in posterior wall diastolic and systolic thickness reflective of compensatory hypertrophy (P < 0.05). Initial infarct size (measured at 24 hours) was not different comparing AS-605240 (29% ± 4%) and vehicle-treated mice (31% ± 1%, P = nonsignificant). At 4 weeks after AMI, infarct size was significantly smaller in the AS-605240-treated mice (14% ± 2%) compared with vehicle-treated mice (28% ± 3%, P < 0.001), reflecting greater infarct resorption.
CONCLUSIONS: Phosphoinositide 3-kinase gamma inhibition with AS-605240 after AMI leads to enhanced infarct resorption, greater compensatory hypertrophy of the nonischemic myocardium, and more favorable cardiac remodeling and function.
Authors:
Ignacio M Seropian; Antonio Abbate; Stefano Toldo; Jessica Harrington; Lisa Smithson; Ramzi Ockaili; Eleonora Mezzaroma; Federico Damilano; Emilio Hirsch; Benjamin W Van Tassell
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  56     ISSN:  1533-4023     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-04-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  651-8     Citation Subset:  IM    
Affiliation:
VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.
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