Abstract 1157: Coronary Endothelial Dysfunction In Mice With Conditional, Cardiomyocyte Specific Overexpression Of The Mineralocorticoid Receptor: Prevention By An Antioxidant Treatment
Deleterious effects of aldosterone excess have been demonstrated in cardiovascular diseases, and they might be linked in part to coronary vascular dysfunction. However, whether such vascular dysfunction is a cause or a consequence of the changes occurring in the cardiomyocytes is unclear. Moreover, the possible link between aldosterone-mediated effects on the cardiomyocyte on one hand and the coronary arteries on the other hand are unknown. Thus, we used a mouse model of conditional, cardiomyocyte-specific overexpression of human mineralocorticoid receptor (MR) (Ouvrard-Pascaud et al., Circulation 2005) and observed its effects on coronary endothelial function. Three months old transgenic (TG) mice were obtained after removing doxycycline treatment used to inhibit lethal embryonic MR overexpression. TG mice and their matched controls (Cont) were either untreated or treated with MR antagonist canrenoate (40 mg/kg/day) or with an antioxidant treatment (vitamin E 1% in chow and vitamin C 0.05% in water) for 1 month. Segments of left coronary arteries (diameter 180 –220 μm) were isolated and mounted in a wire myograph. After pre-contraction with serotonin, we assessed endothelium-mediated (either NO-dependent or independent) relaxations in response to increasing concentrations of acetylcholine (Ach) before and after incubation with a NOSynthase inhibitor (LNNA). Compared to control mice, cardiac MR overexpression induced decreased relaxing responses to Ach either without (maximal relaxation: Cont: 95±4% n=7; TG: 68±8% n=7 p<0.05) or with LNNA (Cont: 19±3% n=7; TG: 5±4% n=7 p<0.05). A one month treatment by canrenoate totally prevented this coronary dysfunction which was also prevented by a one month treatment with vitamin E/vitamin C. The endothelium-independent relaxing responses to the NO-donor sodium nitroprusside were similar in all groups.We thus demonstrate that an increase in MR expression, restricted to cardiomyocytes is sufficient to induce a coronary endothelial dysfunction mostly through an increase in reactive oxygen species production. This suggests for the first time that the phenotypic changes induced by aldosterone within the cardiomyocyte are sufficient to induce per se a secondary coronary vascular dysfunction.