PI3Kγ Inhibition Protects Against Diabetic Cardiomyopathy in Mice

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• 作者：Angelo Maffei^a ; Giuseppe Cifelli^a ; Raimondo Carnevale^a ; Roberta Iacobucci^a ; Fabio Pallante^a ; Valentina Fardella^a ; Stefania Fardella^a ; Emilio Hirsch^b ; Giuseppe Lembo^a ; ^c ; Daniela Carnevale^a ; ^c ; ^{Daniela.carnevale@uniroma1.it}
• 关键词：Diabetes mellitus ; Cardiomyopathy ; Investigational drugs ; PI3Kγ protein ; Mouse
• 刊名：Revista Española de Cardiología (English Edition)
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：70
• 期：1
• 页码：16-24
• 全文大小：3089 K
• 卷排序：70

文摘

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 (PI3Kγ) as a molecular target against diabetic cardiomyopathy, given the role of PI3Kγ 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 PI3Kγ or knock-in for a catalytically inactive PI3Kγ.MethodsMice were made diabetic by streptozotocin. Cardiac function was assessed by serial echocardiographic analyses, while fibrosis and inflammation were evaluated by histological analysis.ResultsDiabetes induced cardiac dysfunction in wild-type mice. Systolic dysfunction was completely prevented, and diastolic dysfunction was partially blocked, in both PI3Kγ knock-out and kinase-dead mice. Cardiac dysfunction was similarly rescued by administration of the PI3Kγ inhibitor GE21 in a dose-dependent manner. These actions of genetic and pharmacological PI3Kγ inhibition were associated with a decrease in inflammation and fibrosis in diabetic hearts.ConclusionsOur study demonstrates a fundamental role of PI3Kγ in diabetic cardiomyopathy in mice and the beneficial effect of pharmacological PI3Kγ inhibition, highlighting its potential as a promising strategy for clinical treatment of cardiac complications of diabetic patients.