Inducible nitric oxide synthase in human diseases

Kröncke, Klaus‐Dietrich; Fehsel, Karin; Kolb‐Bachofen, V.

doi:10.1046/j.1365-2249.1998.00648.x

Cited by 509 publications

(367 citation statements)

References 118 publications

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“…During inflammatory conditions, the rodent (4-6) and human inducible nitric oxide synthase (hiNOS) genes (7,8) are activated by LPS and cytokines. Transcriptional regulation of the hiNOS gene involves transcription factors NF-κB, Stat-1, AP-1, C/EBPβ, KLF6, and NRF (9)(10)(11)(12)(13)(14)(15)(16). Important posttranscriptional mechanisms also regulate hiNOS mRNA stability through RNA binding proteins HuR, TTP, and KSRP (17)(18)(19)(20).…”

mentioning

confidence: 99%

miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes

Guo¹,

Shao²,

Zheng

et al. 2012

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

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Human inducible nitric oxide synthase (hiNOS) gene expression is regulated by transcriptional and posttranscriptional mechanisms. The purpose of this study was to determine whether specific microRNA (miRNA) directly regulate hiNOS gene expression. Sequence analysis of the 496-bp hiNOS 3′-untranslated region (3′-UTR) revealed five putative miR-939 binding sites. The hiNOS 3′-UTR conferred significant posttranscriptional blockade of luciferase activity in human A549, HCT8, and HeLa cells. The hiNOS 3′-UTR also exerted basal and cytokine-stimulated posttranscriptional repression in an orientation-dependent manner. Functional studies demonstrated that transfection of miR-939 into primary human hepatocytes (HCs) significantly inhibited cytokine-induced NO synthesis in a dose-dependent manner that was abrogated by a specific miR-939 inhibitor. MiR-939 (but not other miRNAs) abolished cytokine-stimulated hiNOS protein in human HC, but had no effect on hiNOS mRNA levels. Site-directed mutagenesis of miR-939 bindings sites at +99 or +112 bp in the hiNOS 3′-UTR increased reporter gene expression. Furthermore, intact miR-939 binding sites at +99 or +112 positions were required for posttranscriptional suppression by miR-939. Cytokine stimulation directly increased miR-939 levels in human HC. Transfection of miR-939 inhibitor (antisense miR-939) enhanced cytokine-induced hiNOS protein and increased NO synthesis in vitro in human HC. Finally, cytokine or LPS injection in vivo in mice increased hepatic miR-939 levels. Taken together, these data identify that miR-939 directly regulates hiNOS gene expression by binding in the 3′-UTR to produce a translational blockade. These findings suggest dual regulation of iNOS gene expression where cytokines induce iNOS transcription and also increase miR-939, leading to translational inhibition in a checkand-balance system. nitric oxide | miRNA regulation

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mentioning

confidence: 99%

miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes

Guo¹,

Shao²,

Zheng

et al. 2012

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

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“…The haem is covalently attached to sGC at His-105 of the ␤1 subunit, and it was thought previously that activation of sGC by NO N itric oxide (NO) is a freely diffusible intercellular signaling molecule that mediates a wide variety of physiological effects in the vasculature, central and peripheral nervous systems, and elsewhere (1)(2)(3)(4). At high levels, NO is also a cytotoxic agent, and is implicated in several clinical conditions, ranging from acute disorders such as septic shock and stroke (5,6) to long-term degenerative diseases such as multiple sclerosis and cancer (7,8). Because of its importance in health and disease, the regulation of NO synthesis has been studied extensively.…”

mentioning

confidence: 99%

On the activation of soluble guanylyl cyclase by nitric oxide

Bellamy

Wood

Garthwaite

2001

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

126

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Soluble guanylyl cyclase (sGC) is the major cellular receptor for the intercellular messenger nitric oxide (NO) and mediates a wide range of physiological effects through elevation of intracellular cGMP levels. Critical to our understanding of how NO signals are decoded by receptive cells and translated into a useful physiological response is an appreciation of the molecular and kinetic details of the mechanism by which NO activates sGC. It is known that NO binds to a haem prosthetic group on the receptor and triggers a conformational change that increases the catalysis of cGMP synthesis by several hundred-fold. The haem is covalently attached to sGC at His-105 of the ␤1 subunit, and it was thought previously that activation of sGC by NO occurs in two steps N itric oxide (NO) is a freely diffusible intercellular signaling molecule that mediates a wide variety of physiological effects in the vasculature, central and peripheral nervous systems, and elsewhere (1-4). At high levels, NO is also a cytotoxic agent, and is implicated in several clinical conditions, ranging from acute disorders such as septic shock and stroke (5, 6) to long-term degenerative diseases such as multiple sclerosis and cancer (7,8). Because of its importance in health and disease, the regulation of NO synthesis has been studied extensively. Much less is understood about how NO signals are decoded and translated into downstream physiological effects. The best known NO receptor is the enzyme soluble guanylyl cyclase (sGC), the activity of which results in cGMP accumulation in target cells, but many of the basic properties of sGC activation in cells remain unclear.In its molecular makeup, sGC exists as an ␣␤-heterodimer, but only two isoforms (␣1␤1, ␣2␤1) so far have been shown to exist at the protein level (9, 10). Most enzymological studies to date have been carried out on the widely expressed ␣1␤1 isoform, and it has become clear that sensitivity of the enzyme to NO is conferred by a single haem moiety that is associated with histidine residue 105 (His-105) of the ␤1 subunit. Because haem-free sGC could be activated by protoporphyrin IX, which resembles five-coordinate nitrosyl haem structurally, it was hypothesized that active sGC required a five-coordinate nitrosyl haem complex (11). These and other observations led to the formulation of a two-step model in which NO binds to the sGChaem, forming the six-coordinate complex, and then the bond joining the haem to His-105 breaks, resulting in the fivecoordinate species (12). This second step triggers a conformational change that propagates to the active site, enhancing catalytic efficiency.Recently, a study by Zhao and et al. (13) investigated the subsecond kinetics of sGC activation by NO by using stoppedflow spectroscopy to follow changes in the absorption peak (Soret band) of the haem moiety. As well as providing a clear kinetic description of NO binding, this study made the assertion that the rate of transition from the six-coordinate to the fivecoordinate sGC also depended on NO concentra...

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“…The differences between the immune response in humans and mice also apply to the downstream effectors of IFN-γ. NOS2 in humans is more tightly regulated than in rodents and the production of nitric oxide appears to be weaker in humans than in mice (Kroncke et al 1998). In addition, while mice have 23 IRG genes of which Irgm1 (LRGModel of autophagy-dependent killing of Toxoplasma gondii induced by CD40.…”

Section: Potential Relevance Of Cd40-induced Autophagy In T Gondii Imentioning

confidence: 99%

CD40, autophagy and Toxoplasma gondii

Subauste

2009

Mem. Inst. Oswaldo Cruz

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Inducible nitric oxide synthase in human diseases

Cited by 509 publications

References 118 publications

miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes

miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes

On the activation of soluble guanylyl cyclase by nitric oxide

CD40, autophagy and Toxoplasma gondii

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