Abstract 1483: Aldosterone Prevents Deleterious Effects of Diabetes in Mouse Hearts by a Proangiogenic Effect
Clinical trials have demonstrated the efficacy of aldosterone blockade in heart failure. However, recent reports showed an unexpected worsening of cardiovascular function by aldosterone antagonism in type 2 diabetic patients without heart failure. This suggest that aldosterone could interfere with diabetes on the deterioration of heart function. This work aimed thus to define the consequences of a slight increase (x1,7) of intracardiac aldosterone in diabetic mice. Diabetes (D) was induced in male mice that overexpress the aldosterone synthase in heart (AS) and in wild-type ones (Wt) by streptozotocin injection. Cardiac function was studied by echocardiography at 7 weeks. Cardiac immuno-histology, biochemistry and molecular biology analyses were performed at 8 weeks. After 8 weeks of diabetes the fraction of shortening was decreased in Wt-D mice (−14% vs Wt; p<0.001), but not in the AS-D. The cardiac structure was similar in Wt-D and AS-D mice but the capillaries / cardiomyocyte ratio was decreased in Wt-D only (−20% vs Wt; p<0.005). Capillary rarefaction in Wt-D mice could be due to the VEGFa protein decrease (−40% vs Wt, p<0.05). In contrast, AS-D mice did not exhibit any VEGFa decrease. This maintainance of VEGFa protein expression could thus be responsible for the preservation of capillary density in AS-D mice.These results suggest that cardiac hypoxia, and thus oxidative stress may occur in WT-D. This assumption is supported by the increased mRNA of COX2 (x3; p=0.005), xanthine oxydase (x2.4; p<0.005) and P67-NADPH oxydase (x1.7; p<0.05) in Wt-D compared to Wt mice. This increase was not found in AS-D. Furthermore there was an increase of the superoxide production as well as the protein carbonylation in the Wt-D mice, but not in the AS-D mice. All the effects of aldosterone synthase overexpression were abolished by eplerenone pre-treatment of AS-D mice. Eplerenone pre-treatment has no effects on any parameter measured on the Wt-D mice. In conclusion, aldosterone through a mineralocorticoid receptor dependant mechanism, prevents VEGFa down regulation which allows the preservation of capillary density. This has as a consequence the prevention of an excessive reactive oxygen species production and the preservation of the systolic function in the AS-D mice.