Cytokine-Induced Endothelial Arginase Expression Is Dependent on Epidermal Growth Factor Receptor

Nelin, Leif D.; Chicoine, Louis G.; Reber, Kristina M.; English, B. Keith; Young, Tamara L.; Liu, Yusen

doi:10.1165/rcmb.2005-0039oc

Cited by 51 publications

(62 citation statements)

References 34 publications

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“…Consistent with this hypothesis, increased vascular arginase activity was reported to contribute to decreased endotheliumdependent NO production in pathologic conditions such as hypertension (19,20), atherosclerosis (21), diabetes (22), and erectile dysfunction (23), or in aging (24). Moreover, even though the regulating factors of arginase expression/activity remain largely unknown, it was demonstrated that various proinflammatory cytokines can act as inducers of arginase expression in cultured endothelial cells (18,25,26).…”

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confidence: 78%

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether arginase pathway abnormalities occur in vessels from rats with adjuvant-induced arthritis (AIA), and to determine whether the up-regulation of arginase, which reciprocally regulates nitric oxide synthase (NOS) by competing for the same substrate, L-arginine, contributes to endothelial dysfunction in AIA.Methods. We performed vascular reactivity experiments on thoracic aortic rings from AIA rats and control rats, and we investigated the response of rings to norepinephrine (NE), sodium nitroprusside (SNP), and acetylcholine (ACh). ACh-induced relaxation was evaluated in the presence (or not in the presence) of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), the arginase inhibitor N -hydroxy-nor-Larginine (nor-NOHA), or both. Aortic arginase activity was measured using a spectrophotometric method, and the expression of arginase and endothelial NOS (eNOS) was evaluated by Western blotting.Results. ACh-induced vasodilation was significantly impaired in AIA rats, while the responses to NE and to SNP did not differ from those in control rats. L-NAME reduced ACh-induced vasodilation to a lesser extent in AIA rats than in control rats. Incubation of aortic rings with nor-NOHA enhanced the vascular response to ACh in AIA rats and reversed the effects of L-NAME. Compared with control rats, AIA rats exhibited increased vascular expression of arginase II (by 22%) (P < 0.05) as well as increased arginase activity (by 49%) (P < 0.05), whereas eNOS expression was unchanged. Finally, arginase activity and expression correlated positively with arthritis severity.Conclusion. Our results are consistent with the notion that arginase up-regulation plays a role in AIAassociated endothelial dysfunction. They suggest that arginase might be an attractive new target for treating endothelial dysfunction in arthritis.

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confidence: 78%

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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“…Higher levels and activity of the AII isoform have been detected in several of kinds of cancer in comparison to normal tissue. There is evidencethatsuggestsapossiblerelationshipbetweenreceptors such as the epidermal growth factor receptor (EGFR) andarginaseup-regulation [13].Interestingly,EGFRandestrogenalsohavebeenlinkedtothetranscriptionalregulation ofL-ornithinedecarboxylase(ODC) [14,15],anenzymethat metabolizes ornithine formed by AII to produce putrescine whichisessentialforcellularproliferationanddifferentiation [16]. In this study, we investigated the arginase activity in womenwithbreastcanceranddetermineditsassociationwith diseasestageandpresenceoftheestrogenreceptor(ER).…”

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confidence: 99%

Arginase Activity in Patients with Breast Cancer: An Analysis of Plasma, Tumors, and Its Relationship with the Presence of the Estrogen Receptor

Perez

Olivares²,

Rodriguez

et al. 2012

Onkologie

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Background: Breast cancer is an important cause of cancerrelated death in women. In this pathological condition, arginase plays a role by providing ornithine as a substrate for the biosynthesis of polyamines which are important in tumor progression. The aim of this work was to determine the arginase activity in the plasma and tumors of patients with breast cancer; also, we investigated the relationship between this activity and the presence of the estrogen receptor. Patients and Methods: We evaluated the plasma arginase activity levels in 80 women with breast cancer and 42 healthy control subjects. We also measured the arginase levels in 42 breast cancer biopsies and 42 control tissues. Results: The mean activity of arginase in plasma was higher in breast cancer patients (0.78 nM/min/mg protein ± 0.04; p = 0.001) than in healthy volunteers (0.53 nM/ min/mg protein ± 0.04); however, this difference was indicative of patients in the advanced stages of the disease (n = 38, stage III; p < 0.0001). In addition, we did not find a relationship between the estrogen receptor and arginase activity. Conclusion: Our results show a higher arginase activity in the plasma of patients in the advanced stages of the disease, suggesting that arginase activity could serve as a possible biological marker of breast cancer progression.

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“…Conversely, arginase II is a mitochondrial protein that is not expressed in the liver (8). Both arginase isoforms are expressed in the lung (27). The metabolism of L-arginine by arginase results in the production of L-ornithine and urea.…”

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confidence: 99%

Hypoxia promotes human pulmonary artery smooth muscle cell proliferation through induction of arginase

Chen

Calvert

Cui

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alterations in the metabolism of L-arginine via arginase and nitric oxide synthase play a critical role in the endothelial dysfunction seen in PAH. L-arginine metabolism by arginase produces L-ornithine and urea. L-ornithine is a precursor for polyamine and proline synthesis, ultimately leading to an increase in cellular proliferation. Given the integral role of the smooth muscle layer in the pathogenesis of hypoxia-induced PAH, we hypothesized that hypoxia would increase cellular proliferation via arginase induction in human pulmonary artery smooth muscle cells (hPASMC). We found that arginase II mRNA and protein expression were significantly increased in cultured hPASMC exposed to 1% O 2 for 24 and 48 h, which coincided with an increase in arginase activity at 48 h. There were no hypoxia-induced changes in levels of arginase I mRNA or protein in cultured hPASMC. Exposure to hypoxia resulted in more than one and a half times as many viable cells after 120 h than normoxic exposure. The addition of the arginase inhibitor, S-(2-boronoethyl)-L-cysteine, completely prevented both the hypoxia-induced increase in arginase activity and proliferation in hPASMC. Furthermore, transfection of small interfering RNA (siRNA) targeting arginase II in hPASMC resulted in knockdown of arginase II protein levels and complete prevention of the hypoxia-induced cellular proliferation. These data support our hypothesis that hypoxia increases proliferation of hPASMC through the induction of arginase II. pulmonary hypertension; L-arginine; vascular remodeling PULMONARY ARTERY HYPERTENSION (PAH) is a life-threatening complication of chronic hypoxic lung diseases characterized by vasoconstriction, thrombosis, and the pathogenic hallmark of vascular remodeling that involves all layers of the vessel wall (10, 15). The smooth muscle layer plays an integral role in the pathogenesis of PAH with the extension of smooth muscle into smaller, normally nonmuscular pulmonary arteries within the respiratory acinus, a feature common to all forms of PAH remodeling (10, 25). In addition, pulmonary artery smooth muscle cells (PASMC) markedly proliferate, resulting in decreased luminal diameters and ultimately the obstruction of resistance level pulmonary arteries (10, 32).The L-arginine metabolic pathway has been shown to be important in maintaining vascular tone. L-arginine is the substrate for nitric oxide synthase (NOS) that generates the signaling molecule nitric oxide (NO) with the coproduct L-citrulline (31). Endogenous NO maintains vascular integrity by maintaining vasodilator tone and modulating vascular smooth muscle cell proliferation (12,18,23). Additionally, L-arginine is the substrate for arginase, of which there are two described isoforms (16,24). Arginase I is a cytosolic enzyme that is highly expressed in the liver. Conversely, arginase II is a mitochondrial protein that is not expressed in the liver (8). Both arginase isoforms are expressed in the lung (27). The metabolism of L-arginine by arginase results in the production of L-ornithin...

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Cytokine-Induced Endothelial Arginase Expression Is Dependent on Epidermal Growth Factor Receptor

Cited by 51 publications

References 34 publications

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Arginase Activity in Patients with Breast Cancer: An Analysis of Plasma, Tumors, and Its Relationship with the Presence of the Estrogen Receptor

Hypoxia promotes human pulmonary artery smooth muscle cell proliferation through induction of arginase

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