Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase γ activity in pressure overload-induced cardiac failure.

Background-Signaling from phosphoinositide 3-kinase gamma (PI3K gamma) is crucial for leukocyte recruitment and inflammation but also contributes to cardiac maladaptive remodeling. To better understand the translational potential of these findings, this study investigates the role of PI3K gamma activity in pressure overload-induced heart failure, addressing the distinct contributions of bone marrow-derived and cardiac cells. Methods and Results-After transverse aortic constriction, mice knock-in for a catalytically inactive PI3K gamma (PI3K gamma KD) showed reduced fibrosis and normalized cardiac function up to 16 weeks. Accordingly, treatment with a selective PI3K gamma inhibitor prevented transverse aortic constriction-induced fibrosis. To define the cell types involved in this protection, bone marrow chimeras, lacking kinase activity in the immune system or the heart, were studied after transverse aortic constriction. Bone marrow-derived cells from PI3K gamma KD mice were not recruited to wild-type hearts, thus preventing fibrosis and preserving diastolic function. After prolonged pressure overload, chimeras with PI3K gamma KD bone marrow-derived cells showed slower development of left ventricular dilation and higher fractional shortening than controls. Conversely, in the presence of a wild-type immune system, KD hearts displayed bone marrow-derived cell infiltration and fibrosis at early stages but reduced left ventricular dilation and preserved contractile function at later time points. Conclusions-Together, these data demonstrate that, in response to transverse aortic constriction, PI3K gamma contributes to maladaptive remodeling at multiple levels by modulating both cardiac and immune cell functions. (Circulation. 2011;123:391-399.)