PI3Kγ Inhibition Protects Against Diabetic Cardiomyopathy in Mice

Introduction and objectives: Cardiovascular diseases, including cardiomyopathy, are the major complications in diabetes. A deeper understanding of the molecular mechanisms leading to cardiomyopathy is critical for developing novel therapies. We proposed phosphoinositide3-kinase gamma (PI3K gamma) as a molecular target against diabetic cardiomyopathy, given the role of PI3Kg in cardiac remodeling to pressure overload. Given the availability of a pharmacological inhibitor of this molecular target GE21, we tested the validity of our hypothesis by inducing diabetes in mice with genetic ablation of PI3K gamma or knock-in for a catalytically inactive PI3K gamma. Methods: Mice were made diabetic by streptozotocin. Cardiac function was assessed by serial echocardiographic analyses, while fibrosis and inflammation were evaluated by histological analysis. Results: Diabetes induced cardiac dysfunction in wild-type mice. Systolic dysfunction was completely prevented, and diastolic dysfunction was partially blocked, in both PI3Kg knock-out and kinase-dead mice. Cardiac dysfunction was similarly rescued by administration of the PI3K gamma inhibitor GE21 in a dosedependent manner. These actions of genetic and pharmacological PI3K gamma inhibition were associated with a decrease in inflammation and fibrosis in diabetic hearts. Conclusions: Our study demonstrates a fundamental role of PI3K gamma in diabetic cardiomyopathy in mice and the beneficial effect of pharmacological PI3Kg inhibition, highlighting its potential as a promising strategy for clinical treatment of cardiac complications of diabetic patients. Full English text available from: www.revespcardiol.org/en (C) 2016 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.