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Purpose: Studies have shown that aldosterone would have angiogenic effects, and therefore would be beneficial in the context of cardiovascular diseases. We thus investigated the potential involvement of aldosterone in triggering a cardiac angiogenic response in the context of type-2 diabetes, and the molecular pathways involved.Procedure: 3 week-old male mice, overexpressing aldosterone-synthase (AS), and their controls littermates (WT) were fed with a standard or high fat, high sucrose (HFHS) diet. After 6 months of diet, mice were sacrificed and cardiac samples were assayed by RT-PCR, immuno-blotting and -histology.Findings: HFHS-diet induced type-2 diabetes (D) in WT and AS mice. VEGFa mRNAs were decreased in WT-D (-43%, P<0.05 vs. WT) while increased in AS-D mice (+236%, P<0.01 vs. WT-D). In WT-D hearts, the proapoptotic p38-MAPK was activated (P<0.05 vs. WT and AS-D) whereas Akt activity decreased. The AS-mice, that exhibited a cardiac upregulation of IGF1-R, showed an increase in Akt phosphorylation when diabetic (P<0.05 vs. WT and AS-D). Contrary to WT-D, AS-D hearts did not express inflammatory markers and exhibited a normal capillary density (P<0.05 vs. WT-D)Conclusions: To our knowledge, this is the first study providing new insights into the mechanisms whereby aldosterone prevents diabetes-induced cardiac disorders. [ABSTRACT FROM PUBLISHER]

Introduction: Scarcity of microvessels and deregulation of the renin-angiotensin-aldosterone system contribute to the development of heart failure in diabetes. We showed that cardiac aldosteronism inhibits the onset of cardiomyopathy in type 1 diabetic mice by preventing capillary rarefaction (Messaoudi, 2009). Another promising therapeutic approach to prevent diabetic heart disease is exercise training (Ex). Exercise is beneficial in diabetic cardiomyopathy in human and experimentally. Thus, the objective of the study was to determine whether cardiac aldosterone-induced angiogenesis in type 2 diabetes (D) is used to meet the energy demand associated with Ex, and to identify the mechanisms involved.Methods: 3 weeks old mice overexpressing cardiac aldosterone system (AS) and their controls (WT) were made diabetic by enriched fat and sucrose diet. After 4 months of diet, diabetic mice and their controls were subjected to 2 months of Ex on treadmill (3 sessions/week). Results: Cardiac function was not affected by Ex. The Ex led to cardiac hypertrophy in AS-D-Ex mice (+15 % in AS-D-Ex vs AS-D, P<0.01) while it improved the basic parameters of WT-D-Ex vs WT-D (body weight: -15 %, blood glucose: -15%, resistance to insulin:-50%). Interestingly, the Ex revealed a defect in AS mice: the cumulative distance traveled by AS mice, with or without type 2 D was 30% lower than in WT mice (p < 0.01). In addition, a 75% mortality was observed in AS mice (diabetic or not) submitted to the Ex, in contrast to WT mice. These results demonstrate that AS mice, unfit to Ex, developed a pathological hypertrophy. In contrast to the observed baseline responses, the Ex did not phosphorylate and thus did not activated the Akt pathway in AS-D-Ex mice (NS vs AS-D), signing the absence of activation of the physiological pathway of cardiac hypertrophy.Conclusion: These results demonstrate a deleterious effect of cardiac aldosteronism in response to Ex, regardless of diabetic context, thus underlining that the microangiogenesis observed in the AS-D mice prevented neither the inability to Ex nor mortality. This suggests that the proangiogenic effect of cardiac hyperaldosteronism associated with type 2 diabetes is not enough to cope with this overload of cardiac output associated with the physical exercise. [ABSTRACT FROM AUTHOR]

Notch3, a receptor expressed in vascular smooth muscle cells (VSMC) and pericytes, has a key role in the integrity of resistance arteries by controlling the maturation of VSMC and the arterial differentiation. The goal of the study was to decipher the role of Notch3 in the normal heart and in the response to pressure overload.To reach our objectives, we used adult male C57Bl/6J mice lacking expression of the Notch3 gene (N3-/-). Hypertension was induced by continuous infusion of Angiotensin II (AngII) for 28 days (1μg/kg/min) in WT and N3-/- mice (n>13). The analysis combined with echocardiography analysis, mRNA quantification, western-blot, immuno- and/or histo-morphometry.In basal conditions, N3-/- mice exhibited cardiac hypertrophy (+20%, p<0.001 vs Wild Type, WT) combined with defects at the structure of coronary artery as evidenced by decreased F-actin content in the media (-20%, p<0.05) and decreased density of arterioles (p<0.05).The AngII -induced Hypertension is lower inN3-/- mice (-20%, p<0.05 vs WT +AngII). Despite this blunted systemic effect, N3-/- mice developed a more severe heart failure (HF) compared to WT+AngII mice with lower shortening fraction (-20%, p<0.01), higher cardiac hypertrophy (+35%, p<0.05), and enhanced markers of fibrosis and inflammation [induction of galectin-3 (x3.5, p<0.01)]. The results in N3-/- +AngII mice, which combined the induction of Angiopoïetin 2 mRNA (+70%, p<0.05) and the repression of VEGFa (p<0.05) are in favour of coronary artery destabilization. Interestingly, coronary vessels did not show medial hypertrophy and this lack of adaptive response to hypertension was accompanied by a decreased expression of F-actin and SM actin mRNA (-50%, p<0.01). Moreover a treatment by Notch3 antisens oligonucleotides (ON) of WT +AngII mice impair coronary artery network as suggested by Angiopoïetin 2 induction (p<0.05 vs WT+AngII+ scrambled ON).Altogether, we provide lines of evidence that alterations of Notch3 signaling pathway in the coronary arteries might play a role in the occurrence of HF in response to chronic increase in blood pressure. [ABSTRACT FROM PUBLISHER]