Temporally controlled overexpression of cardiac‐specific PI3Kα‐ a novel transgenic mouse model

Abstract

Cardiac PI3K signaling plays important roles in cardiac growth and is highly regulated during development with highest levels found during the fetal‐neonatal transition period and lowest in the adult. Prolonged constitutive activation of PI3Kα in the heart results in hypertrophy. To examine the impact of temporal overexpression of PI3Kα in the heart, we have engineered a tetracycline transactivator (tet‐off) controlled inducible transgenic mouse model for cardiac‐specific overexpression of PI3Kα. Cardiac PI3K activity and Akt phosphorylation were significantly increased in adult mice after transgene induction following removal of doxycycline for 2 weeks. Heart weight to body weight ratio was not changed and there were no signs of cardiomyopathy. Overexpression of PI3Kα resulted in increased left ventricular (LV) developed pressure, LV dP/dt max and LV dP/dt min, but not heart rate, as assessed in Langendorff hearts. Mice overexpressing PI3Kα also had increases in the levels of Ca2+‐regulating proteins, including the L‐type Ca2+ channels, ryanodine receptors, and SERCA2a. Thus, temporally controlled overexpression of cardiac PI3Kα does not induce hypertrophy or cardiomyopathy but results in increased contractility, probably via increased expression of multiple Ca2+‐regulating proteins. These distinct phenotypes suggest a fundamental difference between transgenic mice with temporal or prolonged activation of cardiac PI3Kα. (NIH 1 P20 RR018728)