Abstract 17621: PI3K? Inhibition Protects From in Diabetic Cardiomyopathy in Mice
Cardiovascular complications, including cardiomyopathy, are the major causes of fatalities in diabetes. The cardiac abnormalities observed, including apoptosis, hypertrophy, [[Unable to Display Character: ﬁ]]brosis, and alterations of cardiomyocytes contractility, lead to left ventricle (LV) dysfunction and are typically mediated by the inflammatory milieu that derives from the altered metabolic profile. One possible explanation for tissue inflammation in the cardiac failure that characterize diabetic cardiomyopathy, is the recruitment of immune cells. A deeper understanding of the molecular mechanisms leading to the pathological cardiac remodeling is critical for the development of novel therapies aimed at ameliorating cardiac dysfunction.
An emerging candidate is phosphoinositide3-kinase gamma(PI3Kgamma), a lipid and protein kinase expressed in both cardiac cells and leukocytes, that we have previously demonstrated to be key in regulating leukocyte migration in other contexts of cardiac remodeling. To dissect the role of PI3Kgamma in diabetic cardiomyopathy, we induced diabetes in PI3Kgamma KO and WT mice, by streptozotocin (STZ) injections. We found that 8-12 weeks STZ-PI3Kγ KO mice were protected from diabetes-induced LV dysfunction, as evidenced by echocardiographic and PV loops analysis, despite hyperglycemia was comparable. Interestingly, this phenotype was accompanied by a reduction of cardiac fibrosis, as evidenced by picrosirius staining, and leukocyte recruitment and macrophage infiltrate (CD11b+, CD68+, F4/80+ cells). More interesting, when we treated STZ-WT mice, with PI3Kgamma inhibitor, echocardiographic and PV loops analysis as well as tissue analysis for fibrosis and immune cells infiltrate, showed a comparable protection from diabetic cardiomyopathy, as compared to STZ-WT mice treated with vehicle alone.
Overall, our data strongly indicate that PI3Kgamma could be a novel target for therapeutic intervention in diabetic cardiomyopathy.
- © 2013 by American Heart Association, Inc.