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Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice.

ABSTRACT: Aging impairs arterial function through oxidative stress and diminished nitric oxide (NO) bioavailability. Life-long caloric restriction (CR) reduces oxidative stress, but its impact on arterial aging is incompletely understood. We tested the hypothesis that life-long CR attenuates key features of arterial aging. Blood pressure, pulse wave velocity (PWV, arterial stiffness), carotid artery wall thickness and endothelium-dependent dilation (EDD; endothelial function) were assessed in young (Y: 5-7 month), old ad libitum (Old AL: 30-31 month) and life-long 40% CR old (30-31 month) B6D2F1 mice. Blood pressure was elevated with aging (P < 0.05) and was blunted by CR (P < 0.05 vs. Old AL). PWV was 27% greater in old vs. young AL-fed mice (P < 0.05), and CR prevented this increase (P < 0.05 vs. Old AL). Carotid wall thickness was greater with age (P < 0.05), and CR reduced this by 30%. CR effects were associated with amelioration of age-related changes in aortic collagen and elastin. Nitrotyrosine, a marker of cellular oxidative stress, and superoxide production were greater in old AL vs. young (P < 0.05) and CR attenuated these increase. Carotid artery EDD was impaired with age (P < 0.05); CR prevented this by enhancing NO and reducing superoxide-dependent suppression of EDD (Both P < 0.05 vs. Old AL). This was associated with a blunted age-related increase in NADPH oxidase activity and p67 expression, with increases in superoxide dismutase (SOD), total SOD, and catalase activities (All P < 0.05 Old CR vs. Old AL). Lastly, CR normalized age-related changes in the critical nutrient-sensing pathways SIRT-1 and mTOR (P < 0.05 vs. Old AL). Our findings demonstrate that CR is an effective strategy for attenuation of arterial aging.

SUBMITTER: Donato AJ

PROVIDER: S-EPMC3772986 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice.

Donato Anthony J AJ Walker Ashley E AE Magerko Katherine A KA Bramwell R Colton RC Black Alex D AD Henson Grant D GD Lawson Brooke R BR Lesniewski Lisa A LA Seals Douglas R DR

Aging cell 20130702 5

Aging impairs arterial function through oxidative stress and diminished nitric oxide (NO) bioavailability. Life-long caloric restriction (CR) reduces oxidative stress, but its impact on arterial aging is incompletely understood. We tested the hypothesis that life-long CR attenuates key features of arterial aging. Blood pressure, pulse wave velocity (PWV, arterial stiffness), carotid artery wall thickness and endothelium-dependent dilation (EDD; endothelial function) were assessed in young (Y: 5- ...[more]

PMID: 23714110

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Project description:Background3',4'-Dihydroxyflavonol (DiOHF) is an effective antioxidant that acutely preserves nitric oxide (NO) activity in the presence of elevated reactive oxygen species (ROS). We hypothesized that DiOHF treatment (7 days, 1 mg/kg per day s.c.) would improve relaxation in mesenteric arteries from diabetic rats where endothelial dysfunction is associated with elevated oxidant stress.Methodology/principal findingsIn mesenteric arteries from diabetic rats there was an increase in ROS, measured by L-012 and 2',7'-dichlorodihydrofluorescein diacetate fluorescence. NADPH oxidase-derived superoxide levels, assayed by lucigenin chemiluminescence, were also significantly increased in diabetic mesenteric arteries (diabetes, 4892±946 counts/mg versus normal 2486±344 counts/mg, n = 7-10, p<0.01) associated with an increase in Nox2 expression but DiOHF (2094±300 counts/mg, n = 10, p<0.001) reversed that effect. Acetylcholine (ACh)-induced relaxation of mesenteric arteries was assessed using wire myography (pEC(50) = 7.94±0.13 n = 12). Diabetes significantly reduced the sensitivity to ACh and treatment with DiOHF prevented endothelial dysfunction (pEC(50), diabetic 6.86±0.12 versus diabetic+DiOHF, 7.49±0.13, n = 11, p<0.01). The contribution of NO versus endothelium-derived hyperpolarizing factor (EDHF) to ACh-induced relaxation was assessed by evaluating responses in the presence of TRAM-34+apamin+iberiotoxin or N-nitro-L-arginine+ODQ respectively. Diabetes impaired the contribution of both NO (maximum relaxation, R(max) diabetic 24±7 versus normal, 68±10, n = 9-10, p<0.01) and EDHF (pEC(50), diabetic 6.63±0.15 versus normal, 7.14±0.12, n = 10-11, p<0.01) to endothelium-dependent relaxation. DiOHF treatment did not significantly affect the EDHF contribution but enhanced NO-mediated relaxation (R(max) 69±6, n = 11, p<0.01). Western blotting demonstrated that diabetes also decreased expression and increased uncoupling of endothelial NO synthase (eNOS). Treatment of the diabetic rats with DiOHF significantly reduced vascular ROS and restored NO-mediated endothelium-dependent relaxation. Treatment of the diabetic rats with DiOHF also increased eNOS expression, both in total and as a dimer.Conclusions/significanceDiOHF improves NO activity in diabetes by reducing Nox2-dependent superoxide production and preventing eNOS uncoupling to improve endothelial function.

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Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice.

Publications

Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice.

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