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Cardiac aldosterone overexpression prevents harmful effects of diabetes in the mouse heart by preserving capillary density

Smail Messaoudi^*,, Paul Milliez^*,, Jane-Lise Samuel^*,, and Claude Delcayre^*,,1

^* INSERM U942, Hopital Lariboisiere, Paris, France;

Paris-Diderot University, Paris, France;

Cardiology Department, Cote de Nacre University Hospital, Caen, France; and

Lariboisiere Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

¹ Correspondence: INSERM U942, Hopital Lariboisiere, 41 Blvd. de la chapelle, 75010 Paris, France. E-mail: claude.delcayre{at}inserm.fr

Recent reports showed an unexpected worsening of endothelial function by aldosterone antagonism in diabetic patients, suggesting that aldosterone could interfere with the detrimental consequences of diabetes on microvasculature and thus on cardiac function. To test this hypothesis, diabetes (D) was induced using streptozotocin in transgenic (Tg) male mice overexpressing aldosterone-synthase in the heart and in wild-type (Wt) mice. Eight weeks after streptozotocin injection, impairment of left ventricular systolic function, measured by echocardiography (fractional shortening), was accompanied by a decrease in capillaries/cardiomyocyte ratio (–20%) and VEGFa expression (–40%) in Wt-D mice compared with normoglycemic littermates. Furthermore, Wt-D mice demonstrated an increase in superoxide production (+100%) and protein carbonylation (+33%), hallmarks of oxidative stress. Except for a slight increase in protein carbonylation, all of these diabetes-associated cardiac alterations were undetectable in Tg-D mice. Fibrosis was induced similarly in both diabetic groups. Eplerenone (an aldosterone antagonist) abolished all of the effects of aldosterone-synthase overexpression but had no effect in Wt-D mice. Thus, aldosterone prevents systolic dysfunction through a mineralocorticoid receptor-dependent mechanism that may include preventing VEGFa down-regulation and maintaining capillary density. Understanding how aldosterone prevents VEGFa down-regulation in experimental diabetes could be important to define new strategies targeting the prevention of a decrease in capillary density.—Messaoudi, S., Milliez, P., Samuel, J.-L., Delcayre, C. Cardiac aldosterone overexpression prevents harmful effects of diabetes in the mouse heart by preserving capillary density.

Key Words: hormone • VEGFa • oxidative stress • streptozotocin • transgenic animal