- 作者：L. Fazal ; F. Azibani ; N. Bihry ; R. Merval ; E. Polidano ; J. Lise Samuel ; C. Delcayre
- 刊名：Diabetes Metabolism
- 出版年：2012
- 出版时间：March, 2012
- 年：2012
- 卷：38
- 期：supp_S2
- 页码：A40
- 全文大小：1K
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 to determine the pathophysiological effects and to study transduction pathways of insulin in the case of a cardiac hyperaldosteronism with or without type 2 diabetes (T2D).Mat¨¦riels et m¨¦thodes
3 week-old mice overexpressing aldosterone synthase (AS), n = 9, and their wild-type (WT) littermates 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 receptor and insulin growth factor receptor, some of these mice (n = 5 for each group) received a dose of insulin (1 UI/kg body weight) 30 minutes before the sacrifice (Shimizu et al, JCI 2010).
R¨¦sultats
After 4 months of HFHSD, both WT-D and AS-D mice had hyperglycemia (+55 % , 56 % , P < 0,05 vs WT and AS, respectively) and body overweight (+20 % , P < 0,001; +30 % , P < 0,05 vs WT and AS, respectively). Both WT and AS displayed glucose intolerance and insulin resistance, but these T2D signs were less prominent in AS-D. Echocardiography did not show any cardiac dysfunction in WT-D and AS-D mice. The RT-PCR revealed an increase in expression of the markers of oxidative stress and inflammation in WT-D group only. Surprisingly, VEGFa and insulin receptor substrate 1 (IRS1) mRNAs were upregulated in AS-D mice (+44 % , P < 0,05 vs WT-D; +20 % P < 0,05 vs AS). Besides, NOS3 (Nitric Oxide Synthase 3) and IRS2 were increased in both diabetic groups. In basal conditions, as shown by the decreased p-AKT/AKT ratio on Western blot the AKT kinase activity was decreased in hearts of WT-D mice only. Interestingly, acute stimulation of AKT by insulin revealed an increase of the p-AKT/AKT ratio in AS-D only.
Conclusion
The results indicate that in mice developing T2D the AKT signaling pathway in heart could be stimulated by insulin only when cardiac hyperaldosteronism was present. This aldosterone-dependent activation of the AKT pathway might play a role in the induction of VEGFa in heart.