Arginase pathway in human endothelial cells in pathophysiological conditions

Bachetti, Tiziana; Comini, Laura; Francolini, Gloria; Bastianon, D.; Valetti, Barbara; Cadei, Moris; Grigolato, Piergiovanni; Suzuki, Hisanori; Finazzi, Dario; Albertini, Alberto; Curello, Salvatore; Ferrari, Roberto

doi:10.1016/j.yjmcc.2004.05.004

Cited by 90 publications

(81 citation statements)

References 36 publications

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“…The results suggest that the Rho/ROCK pathway stimulates arginase II via regulating the enzymatic activity rather than gene expression. This regulatory model of arginase II in human endothelial cells is further supported by a study by Bachetti et al [39], who showed that arginase activity but not gene expression in the cells was increased after 24 hours of stimulation with inflammatory cytokine mixture. The exact regulatory mechanisms of arginase activity in the cells and in atherosclerotic blood vessels remain an interesting topic for future research.…”

Section: Regulation Of Arginase Gene Expression and Activity In Endotsupporting

confidence: 57%

Endothelial arginase: A new target in atherosclerosis

Yang

Ming

2006

Current Science Inc

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Section: Regulation Of Arginase Gene Expression and Activity In Endotsupporting

confidence: 57%

Endothelial arginase: A new target in atherosclerosis

Yang

Ming

2006

Current Science Inc

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“…Arginase II enzymatic activity can be upregulated by thrombin and inflammatory cytokines that are important for atherothrombosis. 47,157 Our study 47 provided the first evidence, suggesting a role of RhoA/ROCK pathway in upregulation of arginase activity in human endothelial cells.…”

Section: An Endogenous Inhibitor Of Enos: Asymmetric Dimethylargininementioning

confidence: 70%

“…155 The primary function of arginase I is thought to be involved in ammonia detoxification, whereas that of arginase II, in biosynthesis of polyamines and the amino acids, ornithine, proline and glutamate, 156 plays a primary role of regulation of endothelial NO production. 47,157 Interestingly, expression and activity of arginase II were found to be increased in human diabetic corpus cavernosum and inhibition of the enzyme enhances NO-dependent relaxation of corpus cavernosum smooth muscle 158,159 suggesting a potential role of arginase II in negative regulation of NO production in diabetic erectile dysfunction. Most recently, an increase in arginase II expression or activity has been implicated in endothelial dysfunction associated with pulmonary hypertension, 160 aging, 161,162 ischemia-reperfusion-induced endothelial dysfunction, 163 aortic coarctation hypertension, 164 salt-induced hypertension 165 and atherosclerosis.…”

Section: An Endogenous Inhibitor Of Enos: Asymmetric Dimethylargininementioning

confidence: 99%

Recent Advances in Understanding Endothelial Dysfunction in Atherosclerosis

Yang

Ming²

2006

Clinical Medicine & Research

178

117

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Over the last two decades, it has become evident that decreased bioavailability of endothelial nitric oxide (NO) produced from endothelial NO synthase (eNOS), referred to as endothelial dysfunction, plays a crucial role in the development and progression of atherosclerosis. Much progress has been made in understanding the mechanisms of decreased endothelial NO bioavailability at the levels of regulation of eNOS gene expression, eNOS enzymatic activity and NO inactivation. Initial studies suggest that increasing eNOS gene expression would improve endothelial NO release in the hope of inhibiting the progression of atherosclerosis. Recent experimental studies, however, do not always support this therapeutic concept and show some evidence that overexpression of eNOS in atherosclerosis may be even harmful for the disease progression.Thus, recent research to improve endothelial function in atherosclerosis has focused on regulation of eNOS enzymatic activity and prevention of NO inactivation by oxidative stress. Since the role of oxidative stress in endothelial NO bioavailability has been reviewed in a large number of comprehensive articles, this article focuses on the relevant regulatory mechanisms of eNOS enzymatic activity that are emerging to play a role in endothelial dysfunction in atherosclerosis.

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“…We considered the possibility that, although the enzyme is reported to require free arginine (20), HNP-1 could be a substrate for bovine liver arginase. HNP-1 (1.4 nmol), mono-ADP-ribosylated-HNP-1 (1 nmol), ADP-ribosylarginine (18 M), and arginine (5 mM) were incubated with manganese-activated arginase (0.7 units) at pH 9.5 (in 200 L, 37°C, 10 min), conditions used for arginase hydrolysis of arginine to ornithine (21). Identification of the products by amino acid analysis and MS revealed ornithine only in the reaction that contained free arginine.…”

Section: Nmol) (D and E)mentioning

confidence: 99%

ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine

Stevens

Levine

Gochuico

et al. 2009

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

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Defensins (e.g., human neutrophil peptides, or HNPs) contribute to innate immunity through diverse actions, including microbial killing; high concentrations are present in the lung in response to inflammation. Arginines are critical for HNP activity, which is decreased by their replacement with ornithine. ADP-ribosyltransferases (ARTs) catalyze transfer of ADP-ribose from NAD to an acceptor arginine in a protein substrate, whereas ADP-ribosylarginine hydrolases release ADPribose. ART1 on the surface of airway epithelial cells ADP-ribosylated HNP-1 specifically on arginines 14 and 24, with ADP-ribosylation altering biological activity. Di-and mono-ADP-ribosylated HNP-1 were isolated from bronchoalveolar lavage fluid (BALF) of patients with asthma and idiopathic pulmonary fibrosis (IPF), suggesting a role for ADP-ribosylation in disease. In the present study, we observed that ART1-catalyzed ADP-ribosylation of HNP-1 in vitro generated a product with ADP-ribose on arginine 24, and ornithine replacing arginine at position 14. We hypothesized that ADP-ribosylarginine is susceptible to a nonenzymatic hydrolytic reaction yielding ornithine. On incubation of di-or mono-ADP-ribosyl-HNP-1 at 37°C, ADP-ribosylarginine was partially replaced by ornithine, whereas ornithine was not detected by amino acid analysis and mass spectrometry of unmodified HNP-1 incubated under the same conditions. Further, ornithine was produced from the model compound, ADPribosylarginine. BALF from an IPF patient contained ADP-ribosyl-HNPornithine as well as mono-and di-ADP-ribosylated HNP-1, consistent with in vivo conversion of arginine to ornithine. Targeted ADPribosylation of specific arginines by transferases, resulting in their replacement with ornithine, is an alternative pathway for regulation of protein function through posttranslational modification.posttranslational modification ͉ NAD ͉ bacterial toxins N eutrophils, a critical component of the innate immune system, are recruited to airways in response to inflammation or infection (1). Neutrophil defensins [human neutrophil peptides (HNPs) 1-3], stored in azurophilic granules, are small cationic peptides whose main function is to defend the lung against pathogenic microorganisms (2). High levels of defensins have been found in patients with inflammatory lung diseases, such as idiopathic pulmonary fibrosis (IPF) (3) and cystic fibrosis (4). In addition to antimicrobial activities and other diverse functions (5), defensins interact with airway epithelial cells, increasing proliferation and stimulating wound repair (6). HNP1-3 are arginine rich and differ in sequence by one amino acid. The salt bridge formed by Arg 5 -Glu 13 and three disulfide bridges are conserved, but not required, for antibacterial activity in vitro (7,8). The arginines in HNP-1 are critical for maintaining activity (9). In addition, the low number of arginines in HD6 (human defensin 6 expressed in Paneth cells) may be responsible for its lack of antibacterial activity (10).Mono-ADP-ribosylation is a posttranslational ...

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Arginase pathway in human endothelial cells in pathophysiological conditions

Cited by 90 publications

References 36 publications

Endothelial arginase: A new target in atherosclerosis

Endothelial arginase: A new target in atherosclerosis

Recent Advances in Understanding Endothelial Dysfunction in Atherosclerosis

ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine

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