Abstract 3206: PI3Kgamma Inhibition Prevents Adverse Cardiac Remodeling After Acute Myocardial Infarction in the Mouse
Purpose. After acute myocardial infarction (AMI), interleukin-1beta (IL-1beta) is upregulated and participates in cardiac remodeling. Phosphoinositide-3 kinase-gamma (PI3K-gamma) generates secondary messengers in response to IL-1. The aim of the current study was to evaluate whether selective blockade of the PI3K-gamma improves ventricular remodeling after MI by inhibiting the IL-1 signaling pathway.
Methods. For assessing proper IL-1 system blockade, adult male ICR mice were pre-treated with AS-605240 (5 mg/kg, i.p) or saline followed by injection with recombinant murine IL-1beta (3 μg/kg). Left ventricular (LV) ejection fraction (EF) was measured at baseline and 4 hours after IL-1beta injection. Subsequently, additional mice (n=12) were randomly assigned to AS-605240 (5 mg/kg/day i.p.) or saline for 14 days following experimental AMI induced by surgical coronary artery ligation. Transthoracic echocardiography was performed at baseline, and at 7, 14 and 28 days after surgery for measuring of LV end-diastolic (LVEDD) and systolic (LVESD) diameters, LV fractional shortening (LVFS) and right ventricular function (tricuspid annular plane systolic excursions). Infarct scar size and apoptosis were also measured at pathology.
Results. IL-1beta induced a transient reduction in LVEF 4 hours after administration (p<0.05 vs Saline). This transient fall was prevented by AS-605240 (p<0.05 vs Saline). After experimental AMI, we observed an increase in the LVEDD and LVESD, and a fall in LVEF and LVFS (p<0.05 vs Sham for all comparisons) at 7, 14 and 28 days. Treatment with AS-605240 lead to a 31% smaller increase in LVEDD and LVESD (p<0.05 vs Saline), a 30% smaller decrease in LVFS (p<0.05 vs Saline) and a 85% smaller decrease in RV function (p<0.05 vs Saline) up to 28 days after MI. At pathology, AS-605240 was associated with a 55% smaller infarct scar (p<0.05 vs Saline), while no significant differences in cardiomyocyte apoptosis at 28 days were noted.
Conclusions. PI3K-gamma inhibition during AMI leads to preservation of viable myocardium and prevents adverse cardiac remodeling and systolic dysfunction. This represents an attractive therapeutic target for the prevention of heart failure following AMI.
This research has received full or partial funding support from the American Heart Association, Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).