Abstract 10813: Chronic Treatment with SIRT1 Activator SRT1720 Ameliorates Age-Associated Vascular Endothelial Dysfunction in B6D2F1 Mice
Background: Vascular endothelial dysfunction develops with aging, reflected by impaired endothelium-dependent dilation (EDD) mediated by oxidative stress and decreases in nitric oxide (NO) bioavailability. SIRT1 activation has been associated with reduced oxidative stress and increased endothelial NO synthase (eNOS) activity. We tested the hypothesis that chronic treatment with SIRT1 activator SRT1720 would improve EDD in older B6D2F1 mice via enhanced NO and improved redox balance.
Methods: SRT1720 (100 mg/kg BW, Sirtris) was administered to old (OS; n=14, 29–31 mo) and young (YS; n=10, 4–7 mo) mice, and vehicle was given to old mice (OV; n=8, 29–31 mo) for 4 weeks via oral gavage. EDD (in vitro carotid artery dilation to acetylcholine, ACh), NO-mediated EDD (ACh ± L-NAME) and endothelium-independent dilation (EID, sodium nitroprusside) were determined in young control mice (YC; n=15, 5–7 mo), YS, OS and OV.
Results: SRT1720 treatment increased aortic SIRT1 protein expression in young (YC: 1.0 ± 0.05, YS: 2.1 ± 0.1 AU, P<0.05) and old (OS: 2.2 ± 0.1, OV: 1.1 ± 0.4 AU, P<0.05) mice, and restored SIRT1 activity in old mice based on expression of acetyl-p53 (YC: 1.0 ± 0.1, OV: 2.4 ± 0.6, OS: 0.6 ± 0.2 AU, P<0.01). Max EDD (YC: 97 ± 1%, OV: 79 ± 7%) and NO-mediated EDD were impaired with aging (P<0.01). SRT1720 restored EDD in old mice (OS: 92 ± 2%, P<0.05) by enhancing NO- and COX-mediated dilation. Administration of TEMPOL, a superoxide dismutase mimetic, showed that SRT1720-induced improvements in EDD were mediated by reduced superoxide. EID did not differ among groups. SRT1720 increased eNOS expression in old mice (YC: 1.0 ± 0.1, OV: 0.8 ± 0.1, OS: 1.2 ± 0.2 AU, P=0.07), and increased the antioxidant enzyme catalase (YC: 1.0 ± 0.2, YS: 2.4 ± 0.4, OS: 4.2 ± 0.6, OV: 1.2 ± 0.3 AU, P<0.05) and reduced activity of the oxidant enzyme NADPH oxidase (YC: 0.177 ± 0.009, YS: 0.109 ± 0.022, OS: 0.106 ± 0.003, OV: 0.176 ± 0.031 mU/ml, P<0.05) in young and old mice.
Conclusions: Chronic treatment with SIRT1 activator SRT1720 improves EDD possibly by reducing oxidative stress and increasing NO- and COX-mediated dilation via normalization of eNOS protein and vascular redox balance. Chronic treatment with SIRT1 activators may be an effective treatment for vascular endothelial dysfunction with aging.
- © 2010 by American Heart Association, Inc.