BACKGROUND: Phosphoinositide 3-kinase gamma (PI3Kγ) is upregulated in the heart during acute myocardial infarction (AMI) potentially contributing to the development and maintenance of heart failure (HF). METHODS: CD-1 male mice were randomly assigned to pharmacologic inhibition of PI3Kγ using AS-605240 (10 mg/kg/day IP) or vehicle (NaCl 0.9%+DMSO 25% solution) for 14 days following 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 (LV) 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 LV cavitary dimensions, a smaller decrease in LV 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=NS). 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: PI3Kγ inhibition with AS-605240 following AMI leads to enhanced infarct resorption, greater compensatory hypertrophy of the non-ischemic myocardium, and more favorable cardiac remodeling and function.
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