Abstract 5143: Pharmacological Inhibition of Phosphoinositide 3-kinase Gamma Suppresses Reparative Neovascularization and Impairs Recovery From Myocardial Infarction
Phosphoinositide 3-kinase gamma (PI3Kγ) is primarily involved in Gi-coupled receptor-mediated signaling controlling innate and adaptive immune response. Recently, PI3Kγ inhibitors have been proposed as anti-inflammatory agents in a wide spectrum of pathologies, including cardiovascular disease. We have shown previously that PI3Kγ plays a pivotal role in vasculogenesis and reparative angiogenesis. Here we aimed to determine whether inhibition of PI3Kγ could be detrimental for recovery from myocardial infarction (MI). MI was induced in CD1 mice by permanent LAD ligation. The PI3Kγ-selective inhibitor AS605240 (AS) or DMSO (control) was injected i.p. daily from 3 days before MI until either 3 or 14 days post-MI. In AS-treated infarcted hearts, echocardiographic measurements carried out at 14 days post-MI showed extensive wall thinning, reduced stroke volume (24.9±2.5 vs. 36.1±3.6 μl, P<0.05), ejection fraction (19.2±1.9 vs. 26.4±3.0%, P<0.05), fractional shortening (9.1±0.9 vs. 12.5±1.5%, P<0.05) and cardiac output (12.1±1.3 vs. 18.0±1.8 ml/min, P<0.05). Histological assessment of fibrosis revealed that infarct size was increased by 1.4 fold (P<0.01 vs. control). In control hearts at 14 days post-MI, the density of capillaries and arterioles in the peri-infarct area increased by 1.3 and 2.6 folds, respectively (P<0.01 vs. remote area for both comparisons). In contrast, neovascularization response in the peri-infarct area of AS-treated hearts was completely suppressed at both capillary and arteriole level. Interestingly, at 3 days post-MI the number of apoptotic microvascular endothelial cells and cardiomyocytes in the peri-infarct area was increased by 2.6 and 2 folds, respectively (P<0.01 vs. control for both comparisons). Furthermore, PI3Kγ inhibition strongly reduced the number of CD45+ MNCs infiltrating the interstitial space (15.8±6.9 vs. 106.9±28.2 cells/mm2, P<0.05) and surrounding arterioles (0.1±0.1 vs. 1.2±0.3 cells/arteriole, P<0.001) of the peri-infarct area at 3 days post-MI. Our results indicate that PI3Kγ is a key modulator of post-infarct remodeling and reparative neovascularization. Caution is recommended when using PI3Kγ inhibitors as anti-inflammatory drugs in patients with coronary heart disease.