Abstract 13828: Phosphoinositide 3-Kinase p110alpha (PI3Kalpha) Protects Against Diabetes-Induced Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy
Activation of phosphoinositide 3-kinase p110alpha isoform (PI3Kalpha) is cardioprotective in several cardiac pathologies. Marked impairment of left ventricular (LV) function characterizes the diabetic heart. The efficacy of PI3Kalpha cardioprotection has however not been sought in the diabetic heart. We tested the hypothesis that PI3Kalpha activation is protective against diabetes-induced LV dysfunction and remodeling in the mouse heart in vivo. Male cardiac-specific, constitutively-active PI3Kalpha transgenic (caPI3Kalpha; increases PI3Kalpha activity), dominant-negative PI3Kalpha transgenic (dnPI3Kalpha; decreases PI3Kalpha activity) and non-transgenic (Ntg) 6-wk old mice received streptozotocin (STZ, 55 mg/kg i.p./day for 5 days) or vehicle, and were followed for 12 weeks. Increases in blood glucose and glycated hemoglobin (GHB) with STZ were comparable among genotypes (see table). LV diastolic dysfunction was evident in Ntg diabetic mice, based on each of echocardiography-derived A wave velocity, deceleration time and E/A ratio, as well as LV end-diastolic pressure (LVEDP) was apparent. This was accompanied by increased cardiomyocyte size, cardiac collagen content and upregulation of LV superoxide in diabetes. These aspects of diabetic cardiomyopathy were significantly prevented in caPI3Kalpha diabetic mice, but were exacerbated in dnPI3Kalpha mice. Notably, the cardioprotection observed in caPI3Kalpha mice was associated with significant suppression of LV superoxide together with increased phosphorylation of the cell survival kinase, Akt. Interestingly, LV superoxide generation was enhanced in dnPI3Kalpha mice even in the absence of diabetes. Together, these findings suggest that targeting the PI3Kalpha pathway may represent a promising new strategy for the treatment of diabetic cardiomyopathy.*P<0.05 and #P<0.01 vs. within-genotype sham, #P<0.05 and ‡P<0.01 vs. STZ Ntg, ^P<0.05 vs Ntg non-diabetic mice (one-way ANOVA)
- © 2010 by American Heart Association, Inc.