eNOS uncoupling and endothelial dysfunction in aged vessels

Yang, Yang‐Ming; Huang, An; Kaley, Gabor; Sun, Dong

doi:10.1152/ajpheart.00230.2009

Cited by 313 publications

(277 citation statements)

References 34 publications

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“…Reduced cofactor availability for eNOS can decrease NO production 19. Previous reports show that OVX significantly lowers plasma NO metabolite [NO x; plasma nitrate+nitrite] levels in rats 55.…”

Section: Discussionmentioning

confidence: 99%

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Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Conley

Roberts

Sharpton

et al. 2017

Molecular Nutrition Food Res

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ScopeStudies suggest diets rich in fruit and vegetables reduce bone loss, although the specific compounds responsible are unknown. Substrates for endogenous nitric oxide (NO) production, including organic nitrates and dietary nitrate, may support NO production in age‐related conditions, including osteoporosis. We investigated the capability of dietary nitrate to improve NO bioavailability, reduce bone turnover and loss.Methods and resultsSix‐month‐old Sprague Dawley rats [30 ovariectomized (OVX) and 10 sham‐operated (sham)] were randomized into three groups: (i) vehicle (water) control, (ii) low‐dose nitrate (LDN, 0.1 mmol nitrate/kg bw/day), or (iii) high‐dose nitrate (HDN, 1.0 mmol nitrate/kg bw/day) for three weeks. The sham received vehicle. Serum bone turnover markers; bone mass, mineral density, and quality; histomorphometric parameters; and fecal microbiome were examined. Three weeks of LDN or HDN improved NO bioavailability in a dose‐dependent manner. OVX resulted in cancellous bone loss, increased bone turnover, and fecal microbiome changes. OVX increased relative abundances of Firmicutes and decreased Bacteroideceae and Alcaligenaceae. Nitrate did not affect the skeleton or fecal microbiome.ConclusionThese data indicate that OVX affects the fecal microbiome and that the gut microbiome is associated with bone mass. Three weeks of nitrate supplementation does not slow bone loss or alter the fecal microbiome in OVX.

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Section: Discussionmentioning

confidence: 99%

“…Aging is associated with decreased endothelial NOS‐dependent NO synthesis and endothelium‐dependent vasodilation, suggesting a possible role for dietary nitrates to support NO production in age‐related conditions like osteoporosis. 19, 20.…”

Section: Introductionmentioning

confidence: 99%

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Conley

Roberts

Sharpton

et al. 2017

Molecular Nutrition Food Res

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“…For instance, senescent human aortic ECs (HAECs) exhibited higher ICAM-1 expression and lower eNOS activity [168]. Accordingly, the eNOS protein isolated from mesenteric arteries in young mice has the dimer configuration, whereas eNOS protein from aged mice was mostly uncoupled to monomers [169]. The same study revealed that eNOS uncoupling contributed to increased superoxide levels in aged vessels and was due to a reduced BH 4 availability [169].…”

Section: The Roles Of H 2 S and No In Agingmentioning

confidence: 94%

“…Accordingly, the eNOS protein isolated from mesenteric arteries in young mice has the dimer configuration, whereas eNOS protein from aged mice was mostly uncoupled to monomers [169]. The same study revealed that eNOS uncoupling contributed to increased superoxide levels in aged vessels and was due to a reduced BH 4 availability [169]. The aging-related EC dysfunction is largely ascribed to oxidative stress and inflammation [170,171].…”

Section: The Roles Of H 2 S and No In Agingmentioning

confidence: 97%

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

Altaany¹,

Moccia²,

Munaron³

et al. 2014

CMC

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The endothelium is a cellular monolayer that lines the inner surface of blood vessels and plays a central role in the maintenance of cardiovascular homeostasis by controlling platelet aggregation, vascular tone, blood fluidity and fibrinolysis, adhesion and transmigration of inflammatory cells, and angiogenesis. Endothelial dysfunctions are associated with various cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and cardiovascular complications of diabetes. Numerous studies have established the antiinflammatory, anti-apoptotic, and anti-oxidant effects of hydrogen sulfide (H 2 S), the latest member to join the gasotransmitter family along with nitric oxide and carbon monoxide, on vascular endothelium. In addition, H 2 S may prime endothelial cells (ECs) toward angiogenesis and contribute to wound healing, aside to its well-known ability to relax vascular smooth muscle cells (VSMCs), thereby reducing blood pressure. Finally, H 2 S may inhibit VSMC proliferation and platelet aggregation. Consistently, a deficit in H 2 S homeostasis is involved in the pathogenesis of atherosclerosis and of hyperglycaemic endothelial injury. Therefore, the application of H 2 S-releasing drugs or using gene therapy to increase endogenous H 2 S level may help restore endothelial function and antagonize the progression of cardiovascular diseases. The present article reviews recent studies on the role of H 2 S in endothelial homeostasis, under both physiological and pathological conditions, and its putative therapeutic applications. Endothelial structure and functionThe endothelium lines the luminal surface of the entire vascular tree and the cardiac chambers, where it is termed endocardium. As a consequence, the endothelium presents a rather broad extension (300 to 1000 m 2 ) and weight (1.5 kg), achieving sizes comparable to other vital organs of the human body [1,2]. The endothelium can, therefore, be regarded as a real "organ spread across the organism" [3] and, as such, not only it is important for the regulation of local tissue functions, but also for maintaining the whole organism homeostasis [4]. Vascular endothelial cells (ECs) possess a polarized architecture: their luminal membrane is directly exposed to hematic constituents and circulating cells, while the basolateral surface is separated from surrounding tissues by a glycoprotein basement membrane -the sub-endothelial basement -which is formed by fibronectin, laminin, and collagen and is secreted by ECs themselves [2].Heterogeneity is, however, the hallmark of endothelium. ECs differ in morphology, function, and gene expression profile, so that even neighbouring cells from the same organ and blood vessel type exhibit distinct features [4]. For instance, vascular ECs may vary in size, shape, thickness and position of the nucleus. Albeit oriented along direction of blood flow, to attenuate the impact of shear stress forces on the vascular wall, microvascular ECs are rather thin (0.1 µm) and spindle-like, whilst their macrovascul...

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“…Superoxide production in mesenteric arteries was assessed by using dihydroethidium (DHE) and an HPLC/fluorescence detector-based assay to detect 2-hydroxyethidium (2-EOH), a superoxide-induced oxidative product of DHE (15,55). Isolated mesenteric arteries were incubated in control media and in the presence of 0.3 and 1 mmol/l Met, and Met (1 mmol/l) plus enalapril (100 mol/l, ACE inhibitor), losartan (10 M), or 3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine (VAS2870, 5 M, a selective inhibitor of NADPH oxidase; Enzo Life Sciences) for 24 h, respectively.…”

Section: Animals and Vesselsmentioning

confidence: 99%

Role of homocysteinylation of ACE in endothelial dysfunction of arteries

Huang

Pinto

Froogh

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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The direct impact of de novo synthesis of homocysteine (Hcy) and its reactive metabolites, Hcy-S-S-Hcy and Hcy thiolactone (HCTL), on vascular function has not been fully elucidated. We hypothesized that Hcy synthesized within endothelial cells affects activity of angiotensin-converting enzyme (ACE) by direct homocysteinylation of its amino-and/or sulfhydryl moieties. This covalent modification enhances ACE reactivity toward angiotensin II (ANG II)-NADPH oxidase-superoxide-dependent endothelial dysfunction. Mesenteric and coronary arteries isolated from normal rats were incubated for 3 days with or without exogenous methionine (Met, 0.1-0.3 mM), a precursor to Hcy. Incubation of arteries in Met-free media resulted in time-dependent decreases in vascular Hcy formation. By contrast, vessels incubated with Met produced Hcy in a dose-dependent manner. There was a notably greater de novo synthesis of Hcy from endothelial than from smooth muscle cells. Enhanced levels of Hcy production significantly impaired shear stress-induced dilation and release of nitric oxide, events that are associated with elevated production of vascular superoxide. Each of these processes was attenuated by ANG II type I receptor blocker or ACE and NADPH oxidase inhibitors. In addition, in vitro exposure of purified ACE to Hcy-S-S-Hcy/HCTL resulted in formation of homocysteinylated ACE and an enhanced ACE activity. The enhanced ACE activity was confirmed in isolated coronary and mesenteric arteries that had been exposed directly to Hcy-S-S-Hcy/HCTL or after Met incubation. In conclusion, vasculature-derived Hcy initiates endothelial dysfunction that, in part, may be mediated by ANG II-dependent activation of NADPH oxidase in association with homocysteinylation of ACE.

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eNOS uncoupling and endothelial dysfunction in aged vessels

Cited by 313 publications

References 34 publications

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

Role of homocysteinylation of ACE in endothelial dysfunction of arteries

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