PI3K alpha Has a Role in Myocardial Insulin Signaling and Recovery From Cre/Tamoxifen Cardiotoxicity, but is not Required for Normal Function in the Adult Mouse Heart

Introduction: PI3K inhibitors are a promising new therapy for cancer treatment now in clinical trials. However, loss of PI3K isoforms have negative consequences in some models of heart disease. Also, a genetic model with PI3Kα deletion using tamoxifen/Cre had reduced heart function, suggesting a role for PI3Kα in heart contractility; however, those findings may have been compounded by tamoxifen/Cre toxicity. Methods and Results: Cardiomyocyte specific deletion of PI3Kα was achieved with Mer-Cre-Mer (MCM) transgenic mice and tamoxifen administration (40 or 60 mg/kg/day*4days; LD (low dose), HD (high dose)) at 10-11weeks old to induce gene deletion, with function assessed by echocardiography. MCM mice developed systolic dysfunction and atrial dilation at 10 days after the start of HD tamoxifen treatment. Control hearts recovered at 28 days, but PI3Kα deletion hearts had sustained dysfunction and elevated expression of disease markers. Reduced tamoxifen treatment (LD) did not cause heart dysfunction or elevated disease markers but did cause increased ERK activation, as well as effective reduction of PI3Kα protein similar to HD tamoxifen. Deletion of PI3Kα using a constitutively active Cre (Cre) model was assessed for for heart function and insulin signaling as an indicator of PI3Kα activity. Cre PI3Kα knockouts had normal function and elevated ERK activation and blunted insulin signaling. Cardiomyocytes isolated from non-failing human donor hearts and adult mouse cardiomyocytes were treated with the PI3Kα inhibitor BYL-719 (100 nM). Insulin (10 mg/L) mediated Akt activation in both mouse and human cardiomyocytes was blocked by BYL-719. Mice treated with BYL-719 (30 mg/kg/day*2 wks) were assessed for heart function with echocardiography and invasive pressure-volume catheter as well as changes in insulin signaling. Treatment with BYL-719 in mice blocked insulin mediated Akt activation in the heart, caused weight loss and elevated fasting glucose levels, but did not affect heart function. Conclusions: PI3Kα is not essential for maintained function of the adult heart, but has an important role in metabolic signaling and is protective against Cre/tamoxifen toxicity. Our data justifies caution when using PI3Kα inhibitors in cancer patients.