Abstract 17961: A Dual PI3K-mTOR Inhibitor Induced Cardiac Hypertrophy in Mice
Studies from us and others have shown that mice with cardiomyocyte-specific overexpression of a dominant negative PI3Kp110α had smaller hearts but maintained normal cardiac function. Yet, these mice developed systolic heart failure in the presence of cardiac stress, such as doxorubicin and aortic stenosis. Currently, drugs targeting the PI3K pathway are being tested in clinical trials for cancer therapy. Therefore, it is important to assess the cardiac effects of pharmacological inhibition of this pathway. Here, we show that a dual PI3K-mTOR inhibitor, BEZ235 (BEZ), induced cardiac hypertrophy and subsequent heart failure in mice when it was used alone or in combination with chemotherapy drug doxorubicin. This effect of BEZ was associated with increased hepatic gluconeogenesis, hyperglycemia, hyperinsulinemia and increased activation of the IGFR/insulin receptor (IR) in the heart. In isolated cardiomyocytes, BEZ induced feedback activation of IGFR/IR, but this effect was negligible compared to the IGFR/IR activation induced by insulin. Injections of insulin in mice lowered blood glucose, improved glucose and pyruvate tolerance but further increased the activation of IGFR/IR in the heart and aggravated BEZ-induced cardiac dysfunction; whereas OSI-906, an IGFR/IR inhibitor, alleviated this cardiac dysfunction. In addition, low dose Metformin significantly prolonged survival and improved cardiac function in BEZ-treated mice. Taken together, these results identified hyperinsulinemia, a systematic effect of the drug, as one of the mechanisms of BEZ-induced cardiac hypertrophy, arguing animal studies are indispensable for evaluating drug toxicity. They also suggest that Metformin but not insulin may be considered for controlling hyperglycemia and preventing the cardiac side effects caused by PI3K pathway inhibitors in clinic.
Author Disclosures: X. Yan: None. J. Onufrak: None. Y. Yang: None. J. Lee: None. J. Fuseler: None. M. Sun: None. S. Sasi: None. J. Mcdonald: None. L. Hlatky: None. R.L. Price: None. J. Carrozza: None. D. Goukassian: None. T.K. Borg: None. J. Morgan: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.