Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina

Walker, Hamish; McGing, E.; Fisher, Ian; Böger, Rainer H.; Bode‐Böger, Stefanie M.; Jackson, Graham; Ritter, James M.; Chowienczyk, Phil

doi:10.1016/s0735-1097(01)01380-8

Cited by 92 publications

(35 citation statements)

References 39 publications

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“…NO is a vasoprotective molecule that has led to the development of therapies to enhance NO signaling, including dietary L-arginine,1415161718 drug-eluting stents,19 inhalational NO gas,2021 NOS gene therapy,2223 and recently arginase inhibition 1524. Unfortunately, gene therapy remains limited due to problems with the delivery system and vectors, as well as mutational concerns.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological NO donors may contribute to vascular injury prior to initiation of therapy due to surgical manipulation. Moreover, oral L-arginine therapy generated controversial results 151617. On the other hand, inhibition of arginase, a novel therapeutic target, actively augments NO production, and has beneficial effects on cardiac and vascular wall function in atherogenesis, diabetes, and aging 1452427.…”

Section: Discussionmentioning

confidence: 99%

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Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

et al. 2016

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PurposePeroxynitrite plays a critical role in vascular pathophysiology by increasing arginase activity and decreasing endothelial nitric oxide synthase (eNOS) activity. Therefore, the aims of this study were to investigate whether arginase inhibition and L-arginine supplement could restore peroxynitrite-induced endothelial dysfunction and determine the involved mechanism.Materials and MethodsHuman umbilical vein endothelial cells (HUVECs) were treated with SIN-1, a peroxynitrite generator, and arginase activity, nitrite/nitrate production, and expression levels of proteins were measured. eNOS activation was evaluated via Western blot and dimer blot analysis. We also tested nitric oxide (NO) and reactive oxygen species (ROS) production and performed a vascular tension assay.ResultsSIN-1 treatment increased arginase activity in a time- and dose-dependent manner and reciprocally decreased nitrite/nitrate production that was prevented by peroxynitrite scavenger in HUVECs. Furthermore, SIN-1 induced an increase in the expression level of arginase I and II, though not in eNOS protein. The decreased eNOS phosphorylation at Ser1177 and the increased at Thr495 by SIN-1 were restored with arginase inhibitor and L-arginine. The changed eNOS phosphorylation was consistent in the stability of eNOS dimers. SIN-1 decreased NO production and increased ROS generation in the aortic endothelium, all of which was reversed by arginase inhibitor or L-arginine. NG-Nitro-L-arginine methyl ester (L-NAME) prevented SIN-1-induced ROS generation. In the vascular tension assay, SIN-1 enhanced vasoconstrictor responses to U46619 and attenuated vasorelaxant responses to acetylcholine that were reversed by arginase inhibition.ConclusionThese findings may explain the beneficial effect of arginase inhibition and L-arginine supplement on endothelial dysfunction under redox imbalance-dependent pathophysiological conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

et al. 2016

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“…Although the prospect of therapeutic neovascularization is promising, its mechanisms are not completely elucidated, and a long period of exploration and transition to successful clinical trials will be needed 25. Modification and optimization of the vascular environment are crucial for effective neovascularization, and a multimodality approach requiring combinations of protein-, gene-, and cell-based therapies will be the focus of future research 26…”

Section: Resultsmentioning

confidence: 99%

Cardioprotective activity of placental growth factor combined with oral supplementation of L-arginine in a rat model of acute myocardial infarction

Luo¹,

Chen²,

Huang³

et al. 2016

DDDT

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ObjectiveExogenous administration of placental growth factor (PlGF) stimulates angiogenesis and improves ventricular remodeling after acute myocardial infarction (AMI), and supplementation with l-arginine ameliorates endothelial function. The objective of the present study was to compare the cardioprotective effects of combination therapy of PlGF and l-arginine with those of direct administration of PlGF alone in a rat model of AMI.Materials and methodsFifty male Sprague Dawley rats were randomly divided into five groups: sham group, normal saline group, l-arginine group, PlGF group, and combination group (PlGF + l-arginine). An AMI rat model was established by ligation of the left anterior descending of coronary arteries. After 4 weeks of postligation treatment, cardiac function, scar area, angiogenesis and arteriogenesis, myocardial endothelial nitric oxide synthase (eNOS) and collagen I protein content, and plasma concentration of brain natriuretic peptide (BNP) were studied. Echocardiography, Masson’s staining, immunohistochemical analyses, Western blot, and enzyme-linked immunosorbent assay were performed.ResultsLeft ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), and capillary and arteriole densities were higher in the PlGF group than in the normal saline group (P<0.01). Scar area, collagen I protein content, and plasma concentration of BNP were decreased in the PlGF group (P<0.01). Myocardial eNOS protein level was elevated in the l-arginine group and PlGF + l-arginine group (P<0.01). Compared with the PlGF group, LVEF, LVFS, myocardial eNOS, and capillary and arteriole densities were higher in the combination group (P<0.01). Scar area, content of collagen I protein, and plasma concentration of BNP were reduced in the combination group (P<0.01).ConclusionExogenous administration of PlGF stimulates angiogenesis and improves cardiac function. l-arginine increases the expression of the eNOS protein. PlGF and l-arginine have a more pronounced, synergistic protective effect on myocardial protection compared with that of exogenous PlGF therapy alone.

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“…[7][8][9][10][11][12] Taken together, these negative studies suggest that the effect of supplemental L-arginine differs as a function of the species studied, the anatomic location of the lesions analyzed, and the presence or absence of established atherothrombotic disease. This conclusion, however, is not very satisfying in that it fails to address the possible molecular mechanisms by which to explain the inconsistent results.…”

Section: See Page 97mentioning

confidence: 99%

“…25 As one final metabolic derangement to consider, L-arginine can undergo decarboxylation to L-agmatine, which has also been shown to inhibit NO synthases. 26,27 The results of the study by Chen and colleagues 6 together with several other prior studies [7][8][9][10][11][12] suggest that we must temper our enthusiasm for the simple administration of L-arginine to increase the synthesis of NO by eNOS as a means to improve endothelial function and inhibit atherogenesis. In the setting of established atherothrombotic disease, the data for the benefits of L-arginine supplementation are at best inconsistent, and from the theoretical perspective, one can hypothesize rational mechanisms by which L-arginine can worsen existing vascular dysfunction and disease.…”

Section: See Page 97mentioning

confidence: 99%

Adverse Effects of Supplemental l -Arginine in Atherosclerosis

Loscalzo

2003

ATVB

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A therothrombosis and its risk factors are associated with endothelial dysfunction, 1 one manifestation of which is inadequate production of bioactive endothelial NO. Two basic mechanisms account for the loss of endothelial NO: decreased synthesis and increased oxidative inactivation. In the atherothrombotic vessel, both mechanisms appear to be active. Vascular production of reactive oxygen species creates an environment in which NO can be oxidatively inactivated to peroxynitrite and other derivatives. The sources of one of these reactive oxygen speciessuperoxide anion-include NAD(P)H oxidase elaborated on the plasma membrane of leukocytes, endothelial cells, and vascular smooth muscle cells; mitochondria; and the NO synthases. Both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) isoforms are expressed in the atherothrombotic vasculature and, owing to a loss of substrate or reducing cofactors required for NO synthesis, undergo enzymatic "uncoupling" leading to both a loss of NO production and an increase in superoxide anion generation. See page 97The semiessential amino acid L-arginine is the principal substrate of the NO synthases, which catalyze its fiveelectron oxidation to L-citrulline and NO. As early as 1992, Creager and colleagues 2 showed that supplemental dietary L-arginine improved endothelial vasodilator response in hypercholesterolemic subjects, and Dubois-Rande and coworkers 3 showed that intravenous L-arginine improved endothelial vasodilator response in patients with atheromatous left anterior descending coronary arteries. These initial observations were followed by numerous studies supporting the benefits of acute and chronic L-arginine supplementation on endothelial NO production in animal models and human subjects.These studies were all predicated on the view that L-arginine will enhance the production of NO by eNOS, and that eNOS-derived NO is antiatherogenic. In established atherothrombosis, however, iNOS is upregulated, and its expression and activity can promote atherogenesis. The high flux of NO from iNOS in an environment rich in reactive oxygen species, especially superoxide anion, leads to the generation of peroxynitrite. The formation of this oxidant consumes NO, leads to 3-nitration of protein tyrosyl side chains, promotes oxidant stress, and oxidizes tetrahydrobiopterin; this last effect causes uncoupling of the NO synthases, which leads to their serving as additional sources of superoxide anion generation. In support of this mechanism, recent studies of mice with a genetic deficiency of iNOS that were also hyperlipidemic from apolipoprotein E deficiency [iNOS(Ϫ/Ϫ)/apoE(Ϫ/Ϫ)] revealed that the absence of iNOS expression was associated with a decrease in markers of oxidant stress and attenuated atherogenesis. 4,5 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Chen and colleagues 6 continue to explore the relationship between iNOS and atherogenesis by examining the effects of chronic L-arginine treatment on atherosclerotic burden in apoE(Ϫ/Ϫ) and i...

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Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina

Abstract: In men with stable angina, an increase in plasma L-arginine/ADMA ratio after two weeks' oral supplementation with L-arginine is not associated with an improvement in endothelium-dependent vasodilatation, oxidative stress or exercise performance.

Cited by 92 publications

References 39 publications

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

Arginase Inhibition Restores Peroxynitrite-Induced Endothelial Dysfunction via L-Arginine-Dependent Endothelial Nitric Oxide Synthase Phosphorylation

Cardioprotective activity of placental growth factor combined with oral supplementation of L-arginine in a rat model of acute myocardial infarction

Adverse Effects of Supplemental l -Arginine in Atherosclerosis

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