Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.

Clarkson, Patrick; Adams, Mark; Powe, Amanda J.; Donald, Ann; McCredie, Robyn J.; Robinson, JH; McCarthy, Susan; Keech, A.; Celermajer, D.; Deanfield, John

doi:10.1172/jci118632

Cited by 395 publications

(275 citation statements)

References 42 publications

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“…31 In addition, increased ADMA levels 32,33 as well as reduced bioavailability of L-arginine have been found in hypercholesterolemia. 34,35 On the other hand, many studies have suggested that hypercholesterolemia is accompanied by increased oxygen radical stress, which is an important determinant of NO bioavailability. 36 -39 In this respect, the reaction of NO with superoxide and the subsequent formation of peroxynitrite appears to be crucial in determining NO bioavailability.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

Wever

Boer

Hijmering

et al. 1999

ATVB

198

117

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Abstract-In patients with chronic renal failure (CRF), atherosclerosis is a major cause of cardiovascular morbidity and mortality. Generally, atherosclerosis has been associated with a reduced bioavailability of nitric oxide (NO). Experimental studies have indicated the presence of enhanced NO degradation by reactive oxygen species as well as decreased NO production as possible causes for this reduced NO bioavailability. So far, the question whether or not NO production is impaired in patients with CRF has never been investigated. Therefore, we measured whole body NO production in 7 patients with CRF, and in 7 matched healthy subjects. To assess the relative importance of a dysfunction of NO synthase (NOS), we compared the NO production of these patients to that of 2 other groups known to have endothelial dysfunction, ie, 7 patients with familial hypercholesterolemia (FH) who did not yet have signs of clinical cardiovascular disease (all nonsmokers), and 5 cigarette smokers. These groups were also compared with 7 nonsmoking, age-matched healthy subjects. Whole body NO production, determined as in vivo arginine-to-citrulline conversion, was assessed by giving an intravenous infusion of [ 15 N 2 ]-arginine as a substrate for NOS and measuring isotopic plasma enrichment of [15 N]-citrulline by LC-MS. NO production in the CRF patients (0.13Ϯ0.02 mol ⅐ kg -1 ⅐ h -1 ) was significantly lower (PϽ0.05) than in the corresponding control group (0.23Ϯ0.09 mol ⅐ kg -1 ⅐ h -1 ). NO production also tended to be lower in the FH patients (0.16Ϯ0.04 mol ⅐ kg -1 ⅐ h -1 ), but the difference with the corresponding control group did not reach significance (0.22Ϯ0.06 mol ⅐ kg -1 ⅐ h -1 ). In the group of smokers, NO production was similar to that in nonsmokers (0.22Ϯ0.09 mol ⅐ kg -1 ⅐ h -1 ).In conclusion, it is demonstrated for the first time that basal whole body NO production is reduced in patients with CRF. This finding implies that therapeutic interventions to endothelial dysfunction in these patients should be primarily directed toward improvement of NO production. The finding of only a tendency toward reduction of NO production in patients with FH and the absence of a reduction in cigarette smokers suggests that other mechanisms such as enhanced NO degradation may be involved in the decrease of NO bioavailability in these groups. (Arterioscler Thromb Vasc Biol. 1999;19:1168-1172.) Key Words: nitric oxide Ⅲ chronic renal failure Ⅲ atherosclerosis Ⅲ endothelium Ⅲ hypercholesterolemia P remature atherosclerosis is one of the primary causes of morbidity and mortality in patients with chronic renal insufficiency. 1 Over the last decade endothelial dysfunction has been identified as an early mediator in this process. Nitric oxide (NO) is one of the main factors involved in the antiatherosclerotic effects of the endothelium, 2 and chronic renal failure (CRF) has been associated with impaired NO bioavailability in the absence of concomitant risk factors, [3][4][5] even in children. 6,7 However, the finding of a reduced NO bioavailabi...

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

Wever

Boer

Hijmering

et al. 1999

ATVB

198

117

View full text Add to dashboard Cite

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“…Supplementation with arginine in humans has produced conflicting results. In some studies, dietary arginine supplementation results in improved vascular function by providing substrate for eNOS and improving NO production (57)(58)(59). Other studies have not seen an improvement in condition, and harmful effects may occur (23, 60 -62).…”

Section: Figmentioning

confidence: 99%

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

Goodwin

Solomonson

Eichler

2004

Journal of Biological Chemistry

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Although cellular levels of arginine greatly exceed the apparent K m for endothelial nitric-oxide synthase, current evidence suggests that the bulk of this arginine may not be available for nitric oxide (NO) production. We propose that arginine regeneration, that is the recycling of citrulline back to arginine, defines the essential source of arginine for NO production. To support this proposal, RNA interference analysis was used to selectively reduce the expression of argininosuccinate synthase (AS), because the only known metabolic role for AS in endothelial cells is in the regeneration of L-arginine from L-citrulline. Western blot analysis demonstrated a significant and dose-dependent reduction of AS protein as a result of AS small interfering RNA treatment with a corresponding diminished capacity to produce basal or stimulated levels of NO, despite saturating levels of arginine in the medium. Unanticipated, however, was the finding that the viability of AS small interfering RNA-treated endothelial cells was significantly decreased when compared with control cells. Trypan blue exclusion analysis suggested that the loss of viability was not because of necrosis. Two indicators, reduced expression of Bcl-2 and an increase in caspase activity, which correlated directly with reduced expression of AS, suggested that the loss of viability was because of apoptosis. The exposure of cells to an NO donor prevented apoptosis associated with reduced AS expression. Overall, these results demonstrate the essential role of AS for endothelial NO production and cell viability.Nitric oxide (NO) 1 is an important modulator for a wide range of functions including vasodilation of blood vessels, immune system function, angiogenesis, inhibition of leukocyte adhesion and platelet aggregation, gene regulation, and apoptosis (1-3). Moreover, NO has a dual role in cell viability depending on the tissue type and concentration. Either very high or very low concentrations of NO may induce cell death, whereas basal concentrations may inhibit apoptosis (4 -7). Previous work has shown that NO protects against serum starvation-(8), H 2 O 2 -(9), TNF-␣-(10), and oxidized low density lipoprotein-induced apoptosis (11, 12) in endothelial cells.Argininosuccinate synthase (AS), the rate-limiting step (13) in the regeneration of arginine from citrulline, catalyzes the synthesis of argininosuccinate, AMP, and inorganic pyrophosphate from citrulline, ATP, and aspartate. Argininosuccinate is then cleaved by argininosuccinate lyase (AL) to produce Larginine and fumarate. In the liver, AS and AL function together as components of the urea cycle, ultimately to form arginine from citrulline. Although the expression of AS and AL in the liver is high, both enzymes are found in most mammalian tissues, although at significantly lower levels. The discovery of arginine-derived NO, catalyzed by nitric-oxide synthases (NOSs), revealed a second role for AS and AL (1-3). Together with NOS, they function as part of a citrulline-NO cycle where AS and AL convert citrul...

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“…All three have been associated with beneficial effects, including improvements in vascular function, systemic inflammatory profile, local inflammation at lesional sites, and an improved platelet profile (4)(5)(6). However, several clinical investigations, particularly long-term studies, have failed to translate these observations into clinical benefit (e.g., refs.…”

mentioning

confidence: 99%

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Khambata

Ghosh

Rathod

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO 3 − ) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitratefed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.

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Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.

Cited by 395 publications

References 42 publications

Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

Nitric Oxide Production Is Reduced in Patients With Chronic Renal Failure

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

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