Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine

Dooley, A; Gao, Beirong; Bradley, NJ; Abraham, David; Black, Carol M.; Jacobs, Michael; Bruckdorfer, K. R.

doi:10.1093/rheumatology/kei276

Cited by 91 publications

(77 citation statements)

References 43 publications

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“…2 Asymmetric methylarginines, asymmetric dimethylarginine (ADMA), and monomethylarginine are endogenous amino acids found in human plasma that inhibit NO synthesis by competing with arginine at the active site of all 3 isoforms of NO synthase (NOS). 3 High circulating levels of ADMA are a feature of renal failure, 4 cardiovascular diseases, 5 and inflammatory disorders, 6 and levels of this methylarginine predict future adverse events in population cohorts. 7,8 Regulation of asymmetric methylarginine levels is mainly through enzymatic breakdown, a reaction catalyzed by the dimethylarginine dimethylaminohydrolase enzymes (DDAHs) that degrade both ADMA and monomethylarginine .…”

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confidence: 99%

Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure

Caplin

Wang

Slaviero

et al. 2012

ATVB

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Objective-Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure. Methods and Results-In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesisdriven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052). Conclusion-Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure. (Arterioscler Thromb Vasc Biol. 2012;32:2892-2900.)Key Words: alanine-glyoxylate aminotransferase-2 ◼ asymmetric dimethylarginine ◼ hypertension ◼ kidney ◼ NO

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confidence: 99%

Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure

Caplin

Wang

Slaviero

et al. 2012

ATVB

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“…were then reduced to NO in a purge vessel containing potassium iodide (1% in acetic acid) as described earlier 30 to determine NO x .…”

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confidence: 99%

Role of oxidative stress in elevated blood pressure induced by high free fatty acids

Wang

Hou

et al. 2009

Hypertens Res

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The aim of the study is to investigate the possible mechanism of oxidative stress in the high free fatty acids (FFAs)-induced hypertension. Male Sprague-Dawley rat models were established and classified into three groups, namely the control group (NC group), the FFA group, and the N-acetylcysteine (NAC) group. Blood pressure (BP) was recorded. An organ chamber experiment was performed to determine endothelium-dependent/-independent vasodilation (EDV/EIV). Reactive oxygen species (ROS), nitrotyrosine, reduced glutathione hormone (GSH) and NO 2 À /NO 3 À levels were measured in plasma. Endothelial nitric oxide synthase (eNOS) mRNA expression in endothelial cells was evaluated by real-time PCR. The following results were observed: (1) In the FFA group, BP increased after 4 h infusion of Intralipid+heparin. In the NAC group, systolic and diastolic BP remained the same. (2) In the FFA group, the aortic rings tended to show impaired EDV in response to acetylcholine (ACh). There was no difference of EDV response in the NAC and NC groups. (3) In the FFA group, NO 2 À /NO 3 À levels were significantly reduced, and eNOS mRNA expression and activity were significantly decreased compared with the NC group. NAC administration increased eNOS mRNA expression and activity. (4) ROS and nitrotyrosine concentrations in the FFA group were higher than in the NC group, and GSH concentrations in the FFA group were lower than in the NC group. Elevated FFAs can induce elevated BP, potentially through FFA-induced impairment of EDV resulting from decreased eNOS mRNA expression and activity. Oxidative stress may also play an important role in potential mechanisms of this high FFA-induced elevated BP.

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“…Our present work demonstrates that melanin adsorbs NO and mediates oxidation to NO x , with possible epigenetic cones-quences. Although the consequences of these interactions are not well known with respect to keloids, one might gain insight by considering the closely-related case of systemic sclerosis, where imbalances in NO metabolism, type I collagen expression, and the occurrence of nitrated proteins have been known to occur for certain disease states [24][25][26]. Melanin sequestration of NO and its role in generating toxic NO x might have similar effects on normal fibroblasts that could possibly result in their transformation to keloid fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

The Role of Eumelanin in Generating Reactive Oxygen and Reactive Nitrogen in Solution: Possible Relevance to Keloid Formation

Menter¹,

Nokkaew²,

Eatman³

et al. 2013

OJPC

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Recently, nitric oxide (NO) has been implicated as an epigenetic factor in keloids, a scarring disease occurring primarily in dark skinned people who have relatively high amounts of pigment melanin. In this work, we tested whether a melanin-mediated redox reaction involving adsorbed NO and O 2 can couple NO oxidation with O 2 reduction to form reactive oxygen species (ROS) or reactive nitrogen species (RNS) in vitro at pH 7.4. We measured the formation of reactive species that oxidize dihydrorhodamine123 (DHR) to fluorescent rhodamine123 in the presence and absence of sepia melanin. In separate experiments, we monitored NO concentration with 4,5-diaminofluorescein (DAF) by measuring the highly fluorescent NO-adduct, DAF-2T. We attempted to detect peroxynitrite with 5 µM 3-methyl-1,2-cyclopentanedione (MCP), a selective scavenger of peroxynitrite (IC50 = 3.6 µM for ONOO  vs. 63.8 µM and >> 100 µM for NO and respectively). However, MCP itself oxidized DHR. We found that in the absence of NO, melanin itself oxidizes DHR, with no loss of DAF-fluorescence (i.e. no net consumption of NO). In the presence of NO, there was a ~57% loss of DAF fluorescence, indicating that NO x is formed at the expense of NO. The data provided good fit (r 2 = 0.94) to a Langmuir adsorption isotherm, with pseudo first order rate k' = 8.2 × 10

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Abnormal nitric oxide metabolism in systemic sclerosis: increased levels of nitrated proteins and asymmetric dimethylarginine

Abstract: NO formation is increased in patients with primary RP or lSSc, but nitration of proteins and elevated ADMA is a particular feature of dSSc and may reflect abnormal NO regulation and/or contribute to endothelial dysfunction in SSc.

Cited by 91 publications

References 43 publications

Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure

Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure

Role of oxidative stress in elevated blood pressure induced by high free fatty acids

The Role of Eumelanin in Generating Reactive Oxygen and Reactive Nitrogen in Solution: Possible Relevance to Keloid Formation

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