P66SHC KNOCK-OUT PREVENTS ALDOSTERONE INDUCED VASCULAR REMODELING AND DYSFUNCTION

Abstract

Objective: Recent evidences suggested that aldosterone may induce the activation of p66shc in vascular smooth muscle cells. This in vivo study sought to investigate whether aldosterone may induce functional and structural alterations in part through p66shc-dependent manner. Design and method: P66shc−/− mice (14 weeks, 6 per group) and age-matched wild type (WT) control mice were treated or not with aldosterone (300 μg /kg/ day) for 4 weeks. Systolic blood pressure (SBP) was measured by tail-cuff method. Endothelium-dependent and independent relaxations were assessed by concentration-response curves to acetylcholine (1 nM to 100 μM) ± L-NAME (100 μM) and sodium nitroprusside (SNP) (10 nM to 1 mM) respectively, in mesenteric arteries pre-contracted with norepinephrine (10 μM). Media-to-lumen ratio (M/L) and cross sectional area (CSA) were evaluated on pressurized preparations. Results: SBP was similar in WT and p66shc−/− mice before treatment and was significantly increased after 4 weeks of aldosterone treatment in both WT (192.3 ± 4.522 vs 103.3 ± 2.996; p < 0.05) and p66shc−/− mice (176.8 ± 5.313 vs 105.3 ± 1.542; p < 0.05). However the SBP increase was significantly blunted in p66shc−/− mice treated with aldosterone as compared to WT treated mice (176.8 ± 5.313 vs 192.3 ± 4.522, p < 0.05). Acetylcholine-induced vasodilation was similar in WT and p66shc−/− mice and was significantly reduced only in WT after aldosterone treatment. Acetylcholine induced relaxation was blunted by L-NAME in all the groups although at less extent in WT. This suggests that aldosterone may induce endothelial dysfunction only in this group. Endothelium-independent vasodilation was similarly preserved in all the groups. M/L ratio was similar in both WT and p66shc−/− before treatment and was significantly increased by aldosterone only in WT group (p < 0.001). CSA was similar in all the groups. Conclusions: Despite BP increase, aldosterone induced endothelial dysfunction and vascular remodelling only in WT but not in p66shc−/− mice. Thus, p66shc may be involved in the mechanisms of endothelial dysfunction and vascular remodelling induced by aldosterone in the cardiovascular system.