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Rev Esp Cardiol (Engl Ed). 2017 Jan;70(1):16-24. doi: 10.1016/j.rec.2016.04.034. Epub 2016 Jul 13.

PI3Kγ Inhibition Protects Against Diabetic Cardiomyopathy in Mice.

[Article in English, Spanish]

Author information

  • 1Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy.
  • 2Department of Molecular Biotechnologies and Health Sciences, University of Torino, Turin, Italy.
  • 3Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • 4Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Istituto Neurologico Mediterraneo, Pozzilli, Isernia, Italy; Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: Daniela.carnevale@uniroma1.it.

Abstract

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 (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.

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 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.

CONCLUSIONS:

Our 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.

KEYWORDS:

Cardiomyopathy; Diabetes mellitus; Fármacos en investigación; Investigational drugs; Miocardiopatía; Mouse; PI3Kγ protein; Proteína PI3Kγ; Ratón

PMID:
27422446
DOI:
10.1016/j.rec.2016.04.034
[PubMed - in process]
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