The Role of Tetrahydrobiopterin in the Regulation of Neuronal Nitric-oxide Synthase-generated Superoxide

Rosen, Gerald M.; Tsai, Pei Shan; Weaver, John; Porasuphatana, Supatra; Roman, Linda J.; Starkov, Anatoly A.; Fiskum, Gary; Pou, Sovitj

doi:10.1074/jbc.m200853200

Cited by 93 publications

(84 citation statements)

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“…Under these conditions, the enzyme iNOS may play a potential role in accelerating adhesion development by serving as an O 2 À -generating system instead of producing NO, by causing steady state catalysis of NADPH oxidation. 74,75 Increase in O 2 À production as a result of hypoxia may also significantly accelerate adhesion development through its rapid reaction with NO yielding ONOO - (Figure 1). 43,84 Peroxynitrite is a much more toxic reagent and attacks many cellular components, reacting with thiols and iron-sulfur centers, initiating lipid peroxidation, and promoting protein nitration via reactions with peroxidases 85,86 ( Figure 1).…”

Section: Tissue Injury Hypoxia Oxidative Stress and Transcription mentioning

confidence: 99%

Advances in the Pathogenesis of Adhesion Development: The Role of Oxidative Stress

et al. 2014

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Over the past several years, there has been increasing recognition that pathogenesis of adhesion development includes significant contributions of hypoxia induced at the site of surgery, the resulting oxidative stress, and the subsequent free radical production. Mitochondrial dysfunction generated by surgically induced tissue hypoxia and inflammation can lead to the production of reactive oxygen and nitrogen species as well as antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase which when optimal have the potential to abrogate mitochondrial dysfunction and oxidative stress, preventing the cascade of events leading to the development of adhesions in injured peritoneum. There is a significant cross talk between the several processes leading to whether or not adhesions would eventually develop. Several of these processes present avenues for the development of measures that can help in abrogating adhesion formation or reformation after intraabdominal surgery.

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Section: Tissue Injury Hypoxia Oxidative Stress and Transcription mentioning

confidence: 99%

Advances in the Pathogenesis of Adhesion Development: The Role of Oxidative Stress

et al. 2014

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“…Rosen and colleagues [42][43][44] 45 have reported that extracellular SOD is a principal regulator of the endothelium-derived NO bioavailability in conduit arteries, and extracellular SOD has been reported to be upregulated in ANG. 46 However, future studies are necessary to determine the source(s) of H 2 O 2 in these arteries.…”

Section: Nos-dependent No and H 2 O 2 Maintain Vasorelaxation In Smalmentioning

confidence: 99%

Novel Nitric Oxide Synthase–Dependent Mechanism of Vasorelaxation in Small Arteries From Hypertensive Rats

et al. 2007

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Abstract-To determine the mechanism(s) involved in vasorelaxation of small arteries from hypertensive rats, normotensive (NORM), angiotensin II-infused (ANG), high-salt (HS), ANG high-salt (ANG/HS), placebo, and deoxycorticosterone acetate-salt rats were studied. Third-order mesenteric arteries from ANG or ANG/HS displayed decreased sensitivity to acetylcholine (ACh)-induced vasorelaxation compared with NORM or HS, respectively. Maximal relaxations were comparable between groups. Blockade of Ca 2ϩ -activated K ϩ channels had no effect on ANG versus blunting relaxation in NORM (log EC 50 : Ϫ6.8Ϯ0.1 versus Ϫ7.2Ϯ0.1 mol/L). NO synthase (NOS) inhibition abolished ACh-mediated relaxation in small arteries from ANG, ANG/HS, and deoxycorticosterone acetate-salt versus blunting relaxation in NORM, HS, and placebo (% maximal relaxation: ANG: 2.7Ϯ1.8; ANG/HS: 7.2Ϯ3.2; NORM: 91Ϯ3.1; HS: 82.1Ϯ13.3; deoxycorticosterone acetate-salt: 35.2Ϯ17.7; placebo: 79.3Ϯ10.3), indicating that NOS is the primary vasorelaxation pathway in these arteries from hypertensive rats. We hypothesized that NO/cGMP signaling and NOS-dependent H 2 O 2 maintains vasorelaxation in small arteries from ANG. ACh increased NOS-dependent cGMP production, indicating that NO/cGMP signaling is present in small arteries from ANG (55.7Ϯ6.9 versus 30.5Ϯ5.1 pmol/mg), and ACh stimulated NOS-dependent H 2 O 2 production (ACh: 2.8Ϯ0.2 mol/mg; N -nitro-L-arginine methyl ester hydrochlorideϩACh: 1.8Ϯ0.1 mol/mg) in small arteries from ANG. H 2 O 2 induced vasorelaxation and catalase blunted ACh-mediated vasorelaxation. In conclusion, Ca 2ϩ -activated K ϩ channel-mediated relaxation is dysfunctional in small mesenteric arteries from hypertensive rats, and the NOS pathway compensates to maintain vasorelaxation in these arteries through NOS-mediated cGMP and H 2 O 2 production.

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“…Active NOS3 is a homodimer that generates NO and L-citrulline from L-arginine. When exposed to oxidant stress, including peroxynitrite (ONOO -), or deprived of its reducing cofactor tetrahydrobiopterin (BH4) or substrate L-arginine, NOS3 uncouples to the monomeric form that generates O 2 -rather than NO (25,28,29). Uncoupled NOS3 is thought to be a prominent source of endothelial ROS in hypertension (19), neurohormonal stimulation, and hyperglycemia (8), and upon exposure to ONOO - (20).…”

Section: Introductionmentioning

confidence: 99%

Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load

Takimoto¹,

Champion²,

Li³

et al. 2005

J. Clin. Invest.

395

306

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Cardiac pressure load stimulates hypertrophy, often leading to chamber dilation and dysfunction. ROS contribute to this process. Here we show that uncoupling of nitric oxide synthase-3 (NOS3) plays a major role in pressure load-induced myocardial ROS and consequent chamber remodeling/hypertrophy. Chronic transverse aortic constriction (TAC; for 3 and 9 weeks) in control mice induced marked cardiac hypertrophy, dilation, and dysfunction. Mice lacking NOS3 displayed modest and concentric hypertrophy to TAC with preserved function. NOS3 -/-TAC hearts developed less fibrosis, myocyte hypertrophy, and fetal gene re-expression (B-natriuretic peptide and α-skeletal actin). ROS, nitrotyrosine, and gelatinase (MMP-2 and MMP-9) zymogen activity markedly increased in control TAC, but not in NOS3 -/-TAC, hearts. TAC induced NOS3 uncoupling in the heart, reflected by reduced NOS3 dimer and tetrahydrobiopterin (BH4), increased NOS3-dependent generation of ROS, and lowered Ca 2+ -dependent NOS activity. Cotreatment with BH4 prevented NOS3 uncoupling and inhibited ROS, resulting in concentric nondilated hypertrophy. Mice given the antioxidant tetrahydroneopterin as a control did not display changes in TAC response. Thus, pressure overload triggers NOS3 uncoupling as a prominent source of myocardial ROS that contribute to dilatory remodeling and cardiac dysfunction. Reversal of this process by BH4 suggests a potential treatment to ameliorate the pathophysiology of chronic pressure-induced hypertrophy.

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The Role of Tetrahydrobiopterin in the Regulation of Neuronal Nitric-oxide Synthase-generated Superoxide

Abstract: Tetrahydrobiopterin (H 4 B) is a critical element in

Cited by 93 publications

References 50 publications

Advances in the Pathogenesis of Adhesion Development: The Role of Oxidative Stress

Advances in the Pathogenesis of Adhesion Development: The Role of Oxidative Stress

Novel Nitric Oxide Synthase–Dependent Mechanism of Vasorelaxation in Small Arteries From Hypertensive Rats

Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load

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