Loss of Cardiac Phosphoinositide 3-Kinase p110α Results in Contractile Dysfunction

Background-Phosphoinositide 3-kinase (PI3K) p110 alpha plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca(2+) current (I(Ca,L)) through the voltage-dependent L-type Ca(2+) channel (LTCC). The aim of this study was to evaluate whether p110 alpha also controls cardiac contractility by regulating the LTCC. Methods and Results-Genetic ablation of p110 alpha (also known as Pik3ca), but not p110 beta (also known as Pik3cb), in cardiac myocytes of adult mice reduced I(Ca,L) and blocked insulin signaling in the heart. p110 alpha-null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110 alpha decreased I(Ca,L) and contractility in canine myocytes. Inhibition of p110 alpha did not reduce I(Ca,L). Conclusions-PI3K p110 alpha but not p110 beta regulates the LTCC in cardiac myocytes. Decreased signaling to p110 alpha reduces the number of LTCCs on the cell surface and thus attenuates I(Ca,L) and contractility. (Circulation. 2009;120:318-325.)