Involvement of Phosphoinositide 3-Kinase γ in Angiogenesis and Healing of Experimental Myocardial Infarction in Mice

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Abstract
Rationale : Phosphoinositide 3-kinase (PI3K)γ is expressed in hematopoietic cells, endothelial cells (ECs), and cardiomyocytes and regulates different cellular functions relevant to inflammation, tissue remodeling and cicatrization. Recently, PI3Kγ inhibitors have been indicated for the treatment of chronic inflammatory/autoimmune diseases and atherosclerosis. Objective : We aimed to determine PI3Kγ contribution to the angiogenic capacity of ECs and the effect of PI3Kγ inhibition on healing of myocardial infarction (MI). Methods and Results : Human umbilical ECs were treated with a selective PI3Kγ inhibitor, AS605240, or a pan-phosphoinositide 3-kinases inhibitor, LY294002. Both inhibitory treatments and small interfering RNA–mediated PI3Kγ knockdown strongly impaired ECs angiogenic capacity, because of suppression of the PI3K/Akt and mitogen-activated protein kinase pathways. Constitutive activation of Akt rescued the angiogenic defect. Reparative angiogenesis was studied in vivo in a model of MI. AS605240 did not affect MI-induced PI3Kγ upregulation, whereas it suppressed Akt activation and downstream signaling. AS605240 strongly reduced inflammation, enhanced cardiomyocyte apoptosis, and impaired survival and proliferation of ECs in peri-infarct zone, which resulted in defective reparative neovascularization. As a consequence, AS605240-treated MI hearts showed increased infarct size and impaired recovery of left ventricular function. Similarly, PI3K γ-deficient mice showed impaired reparative neovascularization, enhanced cardiomyocyte apoptosis and marked deterioration of cardiac function following MI. Mice expressing catalytically inactive PI3K γ also failed to mount a proper neovascularization, although cardiac dysfunction was similar to wild-type controls. Conclusions : PI3Kγ expression and catalytic activity are involved at different levels in reparative neovascularization and healing of MI.