SIRT‐1 and vascular endothelial dysfunction with ageing in mice and humans

Abstract

Non-technical summary Advancing age is a major risk factor for the development of cardiovascular disease. A key characteristic of older arteries that may lead to cardiovascular disease is reduced endothelial function, characterized by blunted endothelium-dependent dilatation. Sirtuins, specifically sirtuin-1, are proteins linked to increases in lifespan and lower incidence of age-related diseases. We hypothesized that diminished sirtuin-1 with advancing age may alter regulation of a key endothelium dilatory enzyme, nitric oxide synthase. Our findings provide novel translational evidence that sirtuin-1 expression and activity contribute to arterial endothelial dysfunction with ageing and that this may be due to altered nitric oxide synthase activation. Importantly, our results provide further compelling support for sirtuin-1 as a potential therapeutic target for lifestyle and pharmacological interventions aimed at the prevention and treatment of arterial ageing and age-associated cardiovascular diseases.Abstract We tested the hypothesis that reductions in the cellular deacetylase, sirtuin-1 (SIRT-1), contribute to vascular endothelial dysfunction with ageing via modulation of endothelial nitric oxide synthase (eNOS) acetylation/activation-associated nitric oxide (NO) production. In older (30 months, n = 14) vs. young (5-7 months, n = 16) B6D2F1 mice, aortic protein expression of SIRT-1 and eNOS phosphorylated at serine 1177 were lower (both P < 0.05), and acetylated eNOS was 6-fold higher (P < 0.05), whereas total eNOS did not differ (P = 0.65). Acetylcholine (ACh)-induced peak endothelium-dependent dilatation (EDD) was lower in isolated femoral arteries with ageing (P < 0.001). Incubation with sirtinol, a SIRT-1 inhibitor, reduced EDD in both young and older mice, abolishing age-related differences, whereas co-administration with L-NAME, an eNOS inhibitor, further reduced EDD similarly in both groups. Endothelium-independent dilatation to sodium nitroprusside (EID), was not altered by age or sirtinol treatment. In older (64 ± 1 years, n = 22) vs. young (25 ± 1 years, n = 16) healthy humans, ACh-induced forearm EDD was impaired (P = 0.01) and SIRT-1 protein expression was 37% lower in endothelial cells obtained from the brachial artery (P < 0.05), whereas EID did not differ. In the overall group, EDD was positively related to endothelial cell SIRT-1 protein expression (r = 0.44, P < 0.01). Reductions in SIRT-1 may play an important role in vascular endothelial dysfunction with ageing. SIRT-1 may be a key therapeutic target to treat arterial ageing.

Redox-regulating sirtuins in aging, caloric restriction, and exercise

“…Data from human and animal studies revealed that SIRT1 could modulate and deacetylate endothelial nitric oxide synthase (eNOS), which in turn resulted in altered NO production. The acetylation level of aortic eNOS of 30-month-old rats was many times higher than that of young rats [116]. Sirtinol was used to inhibit SIRT1 in this study, and it abolished the ageassociated difference in endothelium-dependent dilatation, and the results gained from the samples of endothelial cells, obtained from the brachial artery of young and old subjects, confirmed that in healthy aging SIRT1 could play a role in endothelial dysfunction [116].…”

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

“…We have previously demonstrated that arterial SIRT1 activity is reduced with aging and contributes to the age‐related impairment in endothelial function (Donato et al ., 2011; Gano et al ., 2014). We and others also have shown that lifelong CR prevents (Csiszar et al ., 2009; Donato et al ., 2013) and short‐term CR reverses (Rippe et al ., 2010) the age‐associated decline in endothelial function and that these effects are associated with enhanced arterial SIRT1 activity.…”

“…In this context, the mammalian SIRT1, one of seven members in the sirtuin family of protein deacetylases/deacylases, is a nicotinamide adenine dinucleotide (NAD + )‐dependent deacetylase that acts as a metabolic energy sensor implicated in several of the beneficial effects of CR, including reduced oxidative stress (Boily et al ., 2008; Merksamer et al ., 2013). Our previous work shows that reduced SIRT1 expression and activity is a key mechanism mediating impaired EDD in aging arteries (Rippe et al ., 2010; Donato et al ., 2011; Gano et al ., 2014), and our recent findings indicate that pharmacological activation of SIRT1 with the compound SRT1720 improves EDD in old mice in part by reducing oxidative stress (Gano et al ., 2014). …”

Beneficial effects of lifelong caloric restriction on endothelial function are greater in conduit arteries compared to cerebral resistance arteries

“…All animal procedures conformed to the Guide to the Care and Use of Laboratory Animals (version 8, revised 2011) and were approved by the Utah Animal Care and Use Committee. Endothelium-dependent dilation: effect of NO and oxidative stress Measurements of EDD and endothelial independent dilation (EID) in isolated carotid arteries and MCAs studied ex vivo were performed using a method previously described in detail Donato et al 2009Donato et al , 2011. Briefly, mice were euthanized by exsanguination via cardiac puncture while under isoflurane anesthesia.…”