SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase

Abstract

Reduced caloric intake decreases arterial blood pressure in healthy individuals and improves endothelium-dependent vasodilation in obese and overweight individuals. The SIRT1 protein deacetylase mediates many of the effects of calorie restriction (CR) on organismal lifespan and metabolic pathways. However, the role of SIRT1 in regulating endothelium-dependent vasomotor tone is not known. Here we show that SIRT1 promotes endotheliumdependent vasodilation by targeting endothelial nitric oxide synthase (eNOS) for deacetylation. SIRT1 and eNOS colocalize and coprecipitate in endothelial cells, and SIRT1 deacetylates eNOS, stimulating eNOS activity and increasing endothelial nitric oxide (NO). SIRT1-induced increase in endothelial NO is mediated through lysines 496 and 506 in the calmodulin-binding domain of eNOS. Inhibition of SIRT1 in the endothelium of arteries inhibits endothelium-dependent vasodilation and decreases bioavailable NO. Finally, CR of mice leads to deacetylation of eNOS. Our results demonstrate that SIRT1 plays a fundamental role in regulating endothelial NO and endothelium-dependent vascular tone by deacetylating eNOS. Furthermore, our results provide a possible molecular mechanism connecting the effects of CR on the endothelium and vascular tone to SIRT1-mediated deacetylation of eNOS.calorie restriction ͉ vasorelaxation ͉ silent information regulator 2 ͉ resveratrol ͉ deacetylation C aloric restriction (CR) is a well recognized nonpharmacological approach to reducing arterial blood pressure. CR not only is capable of independently controlling blood pressure of patients with mild hypertension, but also allows a reduction in the number and dosage of medications used to treat hypertension (1, 2). CR and weight loss resulting from CR also improve endothelium-dependent vascular relaxation in obese and overweight individuals with hypertension (3, 4).In addition, CR prolongs organismal lifespan. In the budding yeast, Saccharomyces cerevisiae, aging of replicating cells is determined by the SIR2 gene (5). Retardation of yeast aging by CR depends on the product of this gene, Sir2 (silent information regulator 2), a class III NAD-dependent histone deacetylase. The mammalian ortholog of Sir2, SIRTUIN 1 (SIRT1), targets histones and many nonhistone proteins (6-10). Resveratrol, a plant polyphenol that stimulates SIRT1 activity (11), activates endothelial nitric oxide synthase (eNOS) (12), improves endothelial function, prevents elevation in blood pressure, and restores vascular eNOS activity in animal models of endothelial dysfunction (13). Hypothesizing that the effects of CR and resveratrol on vascular function are mediated, in part, by SIRT1, we investigated the role of SIRT1 in regulating eNOS activity and endothelium-dependent vascular tone. Results and DiscussionTo determine whether SIRT1 plays an important role in regulating endothelium-dependent vascular tone, vasomotor function of rat aortic rings, in which wild-type SIRT1 or a dominant negative SIRT1 mutant (to inhibit endogenous SIRT1) was adenovi...

Androgen depletion in humans leads to cavernous tissue reorganization and upregulation of Sirt1–eNOS axis

“…This point is of major importance because when eNOS-derived NO bioactivity is reduced, there is an impairment of endothelialdependent relaxation and endothelial dysfunction ensues (Mattagajasingh et al 2007).…”

“…Several studies point to Sirt1 as a chief regulator of NO synthesis in endothelium (Milne et al 2007;Pillarisetti 2008;Potente et al 2007) employing an Akt-mediated pathway of eNOS phosphorylation (Lovren et al 2009) or promoting eNOS catalytic activity through deacetylation of lysines 496 and 506 (Mattagajasingh et al 2007). As NO itself appears to reciprocally activate Sirt1 expression and activity (Ota et al 2007), then Sirt1-eNOS axis emerges as a decisive regulatory mechanism in CC endothelium.…”

“…Likewise, blocking Sirt1 function results in decreased NO bioavailability and inhibited endothelium-dependent vasorelaxation (Mattagajasingh et al 2007). Interestingly, eNOS has also been implicated in the regulation of the expression of Sirt1 (Nisoli et al 2005), and NO itself could act as an inducer of Sirt1 activity in endothelium (Ota et al 2010).…”

Resveratrol, an activator of SIRT1, restores erectile function in streptozotocin-induced diabetic rats

“…In calorierestricted rats, it has been reported that SIRT1 promotes endothelialdependent vasodilation by targeting eNOS for deacetylation, thereby leading to enhanced nitric oxide production in the aorta. 32 Although Fukuhara's research demonstrated that resveratrol improved erectile function in STZ-induced diabetic rats by elevating the level of cyclic guanosine monophosphate, other pathophysiological factors underlying diabetes-induced ED, such as apoptosis and oxidative stress, were not reported. In this study, we demonstrated that resveratrol improved diabetes-induced ED by preventing oxidative stress and suppressing apoptosis.…”

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

“…CR and resveratrol increase endothelial-derived nitric oxide (NO) (Csiszar et al, 2009;Nisoli et al, 2005), an important regulator of vascular relaxation and endothelial senescence (Oemar et al, 1998). Mattagajasingh et al (2007) showed that SIRT1 increases NO through deacetylation of eNOS. Further studies are required to determine whether CR-mediated beneficial functions in vascular senescence result from increased SIRT1.…”