The New α-Amino Acid <i>N</i><sup>ω</sup>-Hydroxy-nor-<scp>l</scp>-arginine:  a High-Affinity Inhibitor of Arginase Well Adapted To Bind to Its Manganese Cluster

Custot, J.; Moali, Catherine; Brollo, Maurice; Boucher, Jl; Delaforge, Marcel; Mansuy, Daniel; Tenu, Jp; Zimmermannjl, Xxxx

doi:10.1021/ja970285o

Cited by 91 publications

(77 citation statements)

References 15 publications

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“…The increase in AHR seems to be caused by three mechanisms: 1) direct inhibition of NOS and following insufficiency of NO (39), 2) the enhanced availability of L-arginine to arginase, and 3) a reduction in NOHA production, with these mechanisms contributing to the increased activity of arginase. NOHA, the intermediate in the NOS-catalyzed reaction leading from L-arginine to NO, is a potent competitive inhibitor of arginase (4,7). This suggests ADMA to be involved in asthma through NOS inhibition and enhancement of arginase activity.…”

Section: Discussionmentioning

confidence: 99%

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Takahashi

Oginö

Takemoto

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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The expression of arginase I has been a focus of research into the pathogenesis of experimental asthma, because arginase deprives nitric oxide synthase (NOS) of arginine and therefore participates in the attenuation of bronchodilators such as nitric oxide (NO). The present study used an intranasal mite-induced NC/Nga mouse model of asthma to investigate the contribution of arginase to the asthma pathogenesis, using an arginase inhibitor, N -hydroxy-nor-L-arginine (nor-NOHA). The treatment with nor-NOHA inhibited the increase in airway hyperresponsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid. NOx levels in the lung were elevated despite suppressed NOS2 mRNA expression. Accompanied by the attenuated activity of arginase, the expression of arginase I at both the mRNA and protein level was downregulated. The levels of mRNA for T helper 2 cytokines such as IL-4, IL-5, and IL-13, and for chemotactants such as eotaxin-1 and eotaxin-2, were reduced. Moreover, the accumulation of inflammatory cells and the ratio of goblet cells in the bronchiole were decreased. The study concluded that the depletion of NO caused by arginase contributes to AHR and inflammation, and direct administration of an arginase inhibitor to the airway may be beneficial and could be of use in treating asthma due to its antiinflammatory and airway-relaxing effects, although it is not clear whether the anti-inflammatory effect is direct or indirect. experimental asthma; arginase inhibitor; nor-NOHA

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Section: Discussionmentioning

confidence: 99%

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Takahashi

Oginö

Takemoto

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Nor-NOHA is an analog of an intermediate in the conversion from L-arginine to NO that is a potent inhibitor of arginase with K i values for arginase I and II of 500 and 50 nmol/L, respectively. 18,19 At the presently used concentration, nor-NOHA is highly specific and does not inhibit eNOS activity. 20 -22 EDV and endothelium-independent vasodilatation was reassessed at 60 and 120 minutes of nor-NOHA infusion.…”

Section: Study Protocolmentioning

confidence: 93%

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

et al. 2012

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Background— Endothelial dysfunction plays an important role in the early development of atherosclerosis and vascular complications in type 2 diabetes mellitus. Increased expression and activity of arginase, metabolizing the nitric oxide substrate l -arginine, may result in reduced production of nitric oxide and thereby endothelial dysfunction. We hypothesized that inhibition of arginase activity improves endothelial function in patients with coronary artery disease (CAD) and type 2 diabetes mellitus. Methods and Results— Three groups of subjects were included: 16 patients with CAD, 16 patients with CAD and type 2 diabetes mellitus (CAD+Diabetes), and 16 age-matched healthy control subjects. Forearm endothelium-dependent and endothelium-independent vasodilatation were assessed with venous occlusion plethysmography before and during intra-arterial infusion of the arginase inhibitor N ω -hydroxy-nor- l -arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also coinfused with the nitric oxide synthase inhibitor ( N G -monomethyl L-arginine). The expression of arginase was determined in the internal mammary artery of patients undergoing bypass surgery. Nor-NOHA markedly increased endothelium-dependent vasodilatation (up to 2-fold) in patients with CAD+Diabetes and CAD ( P <0.001) but not in the control group. N G -monomethyl L-arginine completely inhibited the increase in endothelium-dependent vasodilatation induced by nor-NOHA. Endothelium-independent vasodilatation was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes mellitus. Conclusions— Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes mellitus suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction.

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“…It is produced as an intermediary step when L-arginine is metabolized by the NOS enzymes and is also a direct substrate for NOS [14;15]. Recently, a more potent synthetic analogue of NOHA was identified, N-omega-hydroxy-nor-L-arginine (nor-NOHA) [15][16][17]. This compound increases L-arginine availability by inhibiting arginase activity, but does not directly increase NO or citrulline production as it is not a substrate for NOS [15].…”

Section: Introductionmentioning

confidence: 99%

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

et al. 2008

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Background-Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. Nitric oxide (NO), shown to have protective effects in I/R, is produced by nitric oxide synthase (NOS) from the substrate arginine. The purpose of this study was to determine if nor-NOHA, a novel arginase inhibitor, would be able to increase circulating arginine levels and decrease hepatic damage following warm I/R.

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The New α-Amino Acid N^ω-Hydroxy-nor-l-arginine: a High-Affinity Inhibitor of Arginase Well Adapted To Bind to Its Manganese Cluster

Cited by 91 publications

References 15 publications

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

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The New α-Amino Acid Nω-Hydroxy-nor-l-arginine: a High-Affinity Inhibitor of Arginase Well Adapted To Bind to Its Manganese Cluster

Cited by 91 publications

References 15 publications

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

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The New α-Amino Acid N^ω-Hydroxy-nor-l-arginine: a High-Affinity Inhibitor of Arginase Well Adapted To Bind to Its Manganese Cluster