L-arginine supplementation does not inhibit neointimal formation after coronary stenting in human beings: an intravascular ultrasound study

Dudek, Dariusz; Legutko, Jacek; Heba, Grzegorz; Bartuś, Stanisław; Partyka, Łukasz; Huk, Ihor; Dembińska-Kieć, A.; Kałuża, Grzegorz L.; Dubiel, Jacek S.

doi:10.1016/j.ahj.2003.10.025

Cited by 17 publications

(18 citation statements)

References 17 publications

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“…In addition, clinical studies investigating an oral L-arginine supplement for treatment of vascular diseases has shown conflicting results, including worsened vascular diseases in three long-term studies (Walker et al, 2001;Dudek et al, 2004;Wilson et al, 2007). Currently, however, most studies show arginase inhibition restores endothelial dysfunction (Steppan et al,Fig.…”

Section: Discussionmentioning

confidence: 99%

“…NO has multiple vasoprotective characteristics, which has led researchers to investigate NO-based therapeutics that enhance NO signaling including dietary L-arginine (Blum et al, 2000;Walker et al, 2001;Dudek et al, 2004;Wilson et al, 2007;Boger, 2008), drug-eluting stents (Ansel and Lumsden, 2009), NOS gene therapy (Kibbe and Tzeng, 2000;), and NO inhalation (Ichinose et al, 2004;Griffiths and Evans, 2005); however, these strategies have also been associated with adverse effects such as increased genetic mutations, vascular injury, and systemic NO toxicity. In addition, clinical studies investigating an oral L-arginine supplement for treatment of vascular diseases has shown conflicting results, including worsened vascular diseases in three long-term studies (Walker et al, 2001;Dudek et al, 2004;Wilson et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

Hwang

Lee

Min

et al. 2015

J Pharmacol Exp Ther

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Elevated endothelial arginase activity decreases nitric oxide (NO) production by competing with the substrate L-arginine, previously reported, and reciprocally regulating endothelial nitric oxide synthase (eNOS) activity. Thus, arginase inhibitors may help treat vascular diseases associated with endothelial dysfunction. A screening of metabolites from medicinal plants revealed that (2S)-5,29,59-trihydroxy-7,8-dimethoxy flavanone (TDF) was a noncompetitive inhibitor of arginase. We investigated whether TDF reciprocally regulated endothelial NO production and its possible mechanism. TDF noncompetitively inhibited arginase I and II activity in a dose-dependent manner. TDF incubation decreased arginase activity and increased NO production in human umbilical vein endothelial cells and isolated mouse aortic vessels and reduced reactive oxygen species (ROS) generation in the endothelium of the latter. These TDFmediated effects were associated with increased eNOS phosphorylation and dimerization but not with changes in protein content. Endothelium-dependent vasorelaxant responses to acetylcholine (Ach) were significantly increased in TDF-incubated aortic rings and attenuated by incubation with soluble guanylyl cyclase inhibitor. Phenylephrine-induced vasoconstrictor responses were markedly attenuated in TDF-treated vessels from wild-type mice. In atherogenic-prone ApoE 2/2 mice, TDF attenuated the high-cholesterol diet (HCD)-induced increase in arginase activity, which was accompanied by restoration of NO production and reduction of ROS generation. TDF incubation induced eNOS dimerization and phosphorylation at Ser1177. In addition, TDF improved Ach-dependent vasorelaxation responses and attenuated U46619-dependent contractile responses but did not change sodium nitroprusside-induced vasorelaxation or N-NAME-induced vasoconstriction. The findings suggest that TDF may help treat cardiovascular diseases by reducing pathophysiology derived from HCD-mediated endothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

Hwang

Lee

Min

et al. 2015

J Pharmacol Exp Ther

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“…These properties have led to investigations to develop therapies that enhance NO signaling. NO-based therapeutics under investigation include dietary l-arginine (9)(10)(11)(12)(13), drug-eluting stents (14), inhalational NO gas (15,16), and NOS gene therapy (17,18). Unfortunately gene therapy remains limited by vectors, delivery systems, and mutational concerns.…”

Section: Introductionmentioning

confidence: 99%

Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats

Alef¹,

Vallabhaneni²,

Carchman³

et al. 2011

J. Clin. Invest.

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Vascular disease, a significant cause of morbidity and mortality in the developed world, results from vascular injury. Following vascular injury, damaged or dysfunctional endothelial cells and activated SMCs engage in vasoproliferative remodeling and the formation of flow-limiting intimal hyperplasia (IH). We hypothesized that vascular injury results in decreased bioavailability of NO secondary to dysregulated arginine-dependent NO generation. Furthermore, we postulated that nitrite-dependent NO generation is augmented as an adaptive response to limit vascular injury/proliferation and can be harnessed for its protective effects. Here we report that sodium nitrite (intraperitoneal, inhaled, or oral) limited the development of IH in a rat model of vascular injury. Additionally, nitrite led to the generation of NO in vessels and SMCs, as well as limited SMC proliferation via p21 Waf1/Cip1 signaling. These data demonstrate that IH is associated with increased arginase-1 levels, which leads to decreased NO production and bioavailability. Vascular injury also was associated with increased levels of xanthine oxidoreductase (XOR), a known nitrite reductase. Chronic inhibition of XOR and a diet deficient in nitrate/nitrite each exacerbated vascular injury. Moreover, established IH was reversed by dietary supplementation of nitrite. The vasoprotective effects of nitrite were counteracted by inhibition of XOR. These data illustrate the importance of nitrite-generated NO as an endogenous adaptive response and as a pathway that can be harnessed for therapeutic benefit. IntroductionVascular disease contributes significantly to morbidity and mortality in the developed world (1). Current treatments for this disease process, including surgical bypass and percutaneous interventions, are limited by the formation of intimal hyperplasia (IH) and restenosis (2). IH is an exaggerated healing process initiated by injury and characterized by platelet aggregation, leukocyte chemotaxis, extracellular matrix changes, endothelial cell apoptosis, and vascular SMC proliferation and migration (3). Investigations into vascular biology have led to the association of vascular pathology with decreased bioavailability of NO. NO is endogenously formed in the vascular endothelium by NOS using l-arginine as a substrate (4). The decreased bioavailability may occur secondary to increased consumption of NO by reactive oxygen species within the injured vessel wall or impaired synthesis of NO, possibly via decreased endothelial NO synthase, eNOS uncoupling, or dysregulation of l-arginine metabolism.l-Arginine is an important substrate for both NOS and arginase-1 enzymes, and increased arginase activity can deplete substrate availability for NO production. Interestingly, arginase-1 produces l-ornithine and activates the ornithine decarboxylase

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“…Dudek et al 11,12 initially administered the drug intravenously followed by an oral dose of 6 g/day for 14 days after the angioplasty. Despite the fact that re-obstruction rates and neointimal proliferation were similar, this is a much lower dose than that used in this study.…”

Section: Discussionmentioning

confidence: 99%

Efeito da L-arginina na neoproliferação intimal e no remodelamento arterial após lesão por balão, em ilíacas de coelhos hipercolesterolêmicos

Knopfholz¹,

Précoma²,

Brofman³

et al. 2006

Arq. Bras. Cardiol.

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objective: It has been implied that neointimal proliferation and remodeling are the major causes of restenosis. The objective of this study is to assess the effect of orally administered L-arginine on these two factors in hypercholesterolemic rabbits that had suffered an injury to their iliac arteries caused by a catheter balloon. Methods:The study included nineteen rabbits that were divided in two groups: control (CG) and arginine (AG). There were 19 arteries studied from the control group and 17 in the arginine group. The animals were placed on a 2% hypercholesterolemic diet for 15 days and then submitted to a balloon angioplasty in order to produce a lesion in their iliac arteries. Next, the AG animals were given a 1g/kg/day oral dose of a L-arginine solution. The animals were sacrificed 15 days after the angioplasty procedure and histological artery sections were prepared, stained and fixed. The ratio between the neointimal area (in mm 2 ) and the media layer (in mm 2 ) was used to represent lesion development. In order to determine remodeling, the ratio between the total area of the medial portion of the vessel (greater balloon contact) and the total area of the reference segment of the vessel (less balloon contact) was used.results: Mean neointimal thickness (NI/M) was 0.8151±0.2201 in CG and 0.3296±0.1133 in AG. Remodeling patterns for the two groups studied were similar. conclusion: In the experimental model used, L-arginine was able to reduce intimal tissue thickness in hypercholesterolemic rabbits but did not act on artery remodeling.

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L-arginine supplementation does not inhibit neointimal formation after coronary stenting in human beings: an intravascular ultrasound study

Cited by 17 publications

References 17 publications

A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

A Novel Arginase Inhibitor Derived from Scutellavia indica Restored Endothelial Function in ApoE-Null Mice Fed a High-Cholesterol Diet

Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats

Efeito da L-arginina na neoproliferação intimal e no remodelamento arterial após lesão por balão, em ilíacas de coelhos hipercolesterolêmicos

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