P306Aldosterone activates the insulin-activated AKT pathway in heart of diabetic type 2 mice

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Abstract

Introduction

The pathogenesis of diabetic cardiomyopathy is not fully elucidated. Numerous factors may contribute to the development of heart failure in a diabetic context, including the scarcity of microvasculature and neurohumoral dysregulation, particularly the renin-angiotensin-aldosterone-system. We have previously shown that a modest increase of intracardiac aldosterone prevents the development of cardiomyopathy in mice with type 1 diabetes, possibly through a prevention of cardiac capillary dropout (Messaoudi et al. Faseb J 2009). This study aimed 1- to determine the pathophysiological effects of a cardiac hyperaldosteronism when combined with a type 2 diabetes (T2D).and 2- to study transduction pathways involved.

Methods

3 week-old mice overexpressing aldosterone synthase (AS), n=9 and their littermates (WT) n=5 were fed a high fat, high sucrose diet (HFHSD: 41% fat, 43% carbohydrate) or a standard diet ad libitum. After 4 months of diet, glucose and insulin tolerance tests were performed. Echocardiography was done, mice were sacrificed and tissue samples were used for RT-PCR, for immunoblotting and histological analyses. In addition, to analyze the signaling pathways dependent of the insulin - and IGF-receptors, some of these mice (n = 5 for each group) received insulin (1UI/kg body weight) 30 minutes before the sacrifice (Shimizu et al. JCI 2010).

Results

After 4 months of HFHSD, both WT-D and AS-D mice had hyperglycemia ( + 55%, + 56%, P < 0.05 vs WT and AS, respectively), body overweights ( + 20%, P < 0.001; + 30%, P < 0.05 vs WT and AS, respectively). Both Wt and AS display hyperglycemia test and insulin resistance abnormalities of T2D, but the signs were less prominent in AS-D group. Echocardiography shows no cardiac dysfunction in WT-D and AS-D mice. RT-PCR analysis revealed an increased expression of markers of oxidative stress and inflammation in WT-D group only while VEGFa and insulin receptor substrate 1 (IRS1) mRNAs were upregulated in AS-D mice only ( + 44%, P < 0.05 vs WT-D; + 20% P < 0.05 vs AS). Besides, NOS3 (Nitric Oxide Synthase 3) and IRS2 increased in both diabetic groups. Interestingly, the AKT kinase activity in response to insulin evaluated by the AKT phosphorylation level was blunted in Wt-D mice only.

Conclusion

The results indicate that mice developing T2D for 4 months display unique phenotype according to their genotype. In the presence of cardiac hyperaldosteronism sign of oxidative stress are prevented, VEGFa is up regulated likely via the AKT pathway. Increased cardiac aldosterone has beneficial cardiac effect in both type 1 and Type 2 diabetes.

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