Nitric Oxide: Physiological Roles, Biosynthesis and Medical Uses

Adams, David R.; Brochwicz‐Lewinski, M.; Butler, Anthony R.

doi:10.1007/978-3-7091-6351-1_1

Cited by 19 publications

(19 citation statements)

References 647 publications

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“…Our data suggest that HIF-2a activation in ATMs, in opposite to HIF-1a, is involved in the amelioration of adipose tissue inflammation and insulin resistance in obesity. NO is a signaling molecule to mediate various physiological roles, including vasodilator, neurotransmitter, and muscle relaxer (28). However, excessive NO generation by iNOS is well-known to interfere with insulin signaling in obesity (1,2,29).…”

Section: Discussionmentioning

confidence: 99%

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Choe

Shin

et al. 2014

Diabetes

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In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2α, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2α–overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2α augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2α heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). Moreover, glucose intolerance in HFD-fed Hif-2α heterozygous-null mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2α upon HFD. Taken together, these data suggest that macrophage HIF-2α would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue.

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Section: Discussionmentioning

confidence: 99%

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Choe

Shin

et al. 2014

Diabetes

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“…Superficially the NOS monooxygenation I reaction (the twoelectron oxidation of arginine to NHA) might be expected to be similar to that of P450. Although there is not a consensus mechanism for NOS, Scheme 4 (upper right panel) illustrates a mechanism that is increasingly favoured by a number of groups [48,[99][100][101][102]. The enzyme starts off in the ferric state.…”

Section: Detailed Nos Reaction Mechanismsmentioning

confidence: 99%

“…As ferric NO complexes are generally less stable than the Fe# + NO species, this makes thermodynamic sense as a reaction intermediate. Several possible chemical mechanisms of NO product formation during the monooxygenase II reaction are discussed in detail by Adams et al [100]. An adapted version of the model suggested by Korth et al [106] is illustrated in Scheme 5 (upper right panel) ; however, the experimental evidence at present is not sufficient to discriminate between different mechanisms (especially given the argument as to whether NO or NO − is the ultimate product).…”

Section: Scheme 5 Nos Monooxygenation II Reactionmentioning

confidence: 99%

Nitric oxide synthases: structure, function and inhibition

Alderton

Cooper

Knowles

2001

Biochemical Journal

2,480

1,167

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This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, l-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.

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“…9 It has been suggested that this is due to the ability of some S-nitrosothiols to bind Cu + at the S or N center in the -SNO group and an amino or carboxyl group within the RSNO, leading to the formation of ring complexes. 9,15 These inner-shell complexes have also been proposed 10 as an activation step in the decomposition of RSNOs. However, due to the unstable nature and rapid decomposition of S-nitrosothiols by Cu + , experimental studies on such complexes are difficult.…”

Section: Introductionmentioning

confidence: 95%

Ring Complexes of S-Nitrosothiols with Cu⁺: A Density Functional Theory Study

Baciu

Cho

Gauld

2004

Eur J Mass Spectrom (Chichester)

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The density functional theory (DFT) method B3P86/6-311+G(2df,p) has been employed to investigate the complexes formed upon interaction of Cu(+) with nitrosylated cysteine (CysNO) and its decarboxylated (H(2)NCH(2)CH(2)SNO) and deaminated (HOOCCH(2)CH(2)SNO) derivatives. Optimized structures, relative enthalpies and relative free energies have been calculated and compared. In addition, the effects of binding an H(2)O molecule to the Cu(+) centre in the resulting complexes have also been considered. It is found that the most stable complexes are formed when Cu(+) coordinates to the S-nitrosothiol via S of the SNO group. This results in dramatic lengthenings of the SN bond with concomitant shortening of the NO bond. In contrast, when Cu(+) coordinates via the nitrogen of the SNO group, a shortening of the SN bond with lengthening of the NO bond is observed. These effects are tempered by the electron donating ability of other functional groups also coordinated with the Cu(+) centre in the complexes and on the coordination state of the Cu(+) ion.

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Nitric Oxide: Physiological Roles, Biosynthesis and Medical Uses

Cited by 19 publications

References 647 publications

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Nitric oxide synthases: structure, function and inhibition

Ring Complexes of S-Nitrosothiols with Cu⁺: A Density Functional Theory Study

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Nitric Oxide: Physiological Roles, Biosynthesis and Medical Uses

Cited by 19 publications

References 647 publications

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Nitric oxide synthases: structure, function and inhibition

Ring Complexes of S-Nitrosothiols with Cu+: A Density Functional Theory Study

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Product

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Ring Complexes of S-Nitrosothiols with Cu⁺: A Density Functional Theory Study