Disease relevance of NOS2A

• Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis [1].
• Taken together these data indicate a weak but significant association of the NOS2A locus with susceptibility to cerebral malaria [2].
• RESULTS: HSP patients exhibited a significantly increased frequency of the NOS2A short (8-11) CCTTTn alleles (OR 1.64, 95% CI 1.09-2.47, p=0.017) and genotypes (OR 3.59, 95% CI 1.79-7.20, p=0.0002) compared to controls, particularly when patients with nephritis were compared with controls [3].
• OBJECTIVE: To assess the contribution of 2 polymorphisms within the inducible nitric oxide (NOS2A) promoter region to the susceptibility to Henoch-Schönlein purpura (HSP), and to determine if implications exist with severe systemic complications of HSP, in particular with severe renal involvement and permanent renal dysfunction (renal sequelae) [3].
• OBJECTIVE: To assess the contribution of 2 polymorphisms within the inducible nitric oxide (NOS2A) promoter region to susceptibility to giant cell arteritis (GCA) [4].

Psychiatry related information on NOS2A

• Recently, polymorphisms in the endothelial constitutive nitric oxide synthase 3 (NOS3) and also the inducible nitric oxide synthase gene (NOS2A) have been suggested to lead to increased risk of Alzheimer's disease (AD) or dementia with Lewy bodies [5].
• The overall evaluation of these conflicting effects is important in order to decide whether pharmacological iNOS induction, or alternatively NO donors or L-arginine, may constitute a valid approach to prevent or treat penile fibrosis and vasculogenic erectile dysfunction [6].
• Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation [7].
• Odds ratios (ORs), interaction index (gamma), and 95% confidence intervals for the combined effects of iNOS genotype and H pylori infection, cigarette smoking or alcohol drinking were estimated [8].
• Because SHR has been used as a model of vascular dementia and hippocampus is essential for spatial learning and memory, understanding of altered HO/CO and NOS/NO systems in the hippocampus of adult SHR may shed light on the pathogenic development of memory deficits associated with vascular dementia [9].

High impact information on NOS2A

• Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction [10].
• Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response [10].
• NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone [11].
• In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS) [11].
• NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively [12].

Chemical compound and disease context of NOS2A

• Work by others has confirmed these findings in vivo: inhibition of NO synthase [NOS; L-arginine, NADPH: oxygen oxidoreductase (NO-forming), EC 1.14.13.39] in normal rats is followed by increased bone resorption reflected by a marked loss in bone mineral density [13].
• OBJECTIVE: To measure levels of salivary nitrite (NO2-) and to localize nitric oxide synthases (NOS) in the labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS) [14].
• Nitric oxide, iNOS, and inflammation in cystic fibrosis [15].
• Here we assessed changes in NO production induced by 17beta-estradiol (E2) in cells of neuronal origin using human SK-N-SH neuroblastoma cells, which we show express all three isoforms of NOS [16].
• Together these data reveal that constitutive NOS activities are responsible for E2-induced NO production in neuroblastoma cells and that differential activation of NOS isoforms in these cells occurs in response to different treatments [16].

Biological context of NOS2A

• Moreover, IL1R2 (P=0.002 in Blacks), NOS2A (P<0.001 in Whites) and OPRM1 (P=0.004 in Hispanics) gene haplotypes were associated with PTD in specific ethnic groups but not at global significance level [17].
• In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families [1].
• Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility [1].
• NOS2A promoter genotype frequencies (n=715: 358 cases, 357 control subjects) were 0.3%, 16.8%, 83.0% and 0.3% 17.6% and 82.1% for +/+, +/- and -/- genotypes (p=0.952) [18].
• Specifically, for nitric oxide synthase (NOS2A Ser608Leu, rs2297518) Leu/Leu homozygotes, there was a 2-fold risk increase for NHL (OR=2.2, 95% CI=1.1-4.4) (referent=Ser/Ser and Ser/Leu) [19].

Anatomical context of NOS2A

• A significant gene-gene interaction between FCER1B 237Gly and NOS2A D346D was detected, with individuals carrying the minor allele for both polymorphisms having the lowest cord blood IL-13 levels [20].
• Using Western blot analysis and an antibody to the conserved region of nitric oxide synthase (NOS), we have observed up-regulation of NOS, one of the "key players" of inflammation, in chondrocytes of OA-affected patients [21].
• These findings support the hypothesis that activated islet macrophages may mediate beta cell damage during the development of insulin-dependent diabetes by releasing IL-1 in human islets followed by cytokine-induced iNOS expression by beta cells [22].
• We conclude that inflammatory cytokines increase NOS activity in cultured human endothelial cells by increasing tetrahydrobiopterin levels in the face of falling total enzyme; similar regulation appears possible in vivo [23].
• We have examined cytokine regulation of nitric oxide synthase (NOS) in human umbilical vein endothelial cells (HUVEC) [23].

Associations of NOS2A with chemical compounds

• Treatment of human islets with a combination of tumor necrosis factor (TNF) + lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) stimulates inducible nitric oxide synthase (iNOS) expression, nitric oxide production, and inhibits glucose-stimulated insulin secretion [22].
• In contrast to PGE2, a stable analog of PGI2, carba prostacyclin, enhanced IL-1 beta-induced iNOS mRNA levels and nitrite production [24].
• In contrast, the nonselective NOS inhibitor NG-monomethyl-L-arginine inhibits resorption by untreated neonatal rat osteoclasts [13].
• Like other NOS isoforms, recognition sites for FMN, FAD, and NADPH are present, as well as a consensus calmodulin binding site [25].
• The iNOS inhibitor aminoguanidine markedly enhances in vitro resorption by activated NOS-rich chick osteoclasts and by normal rat osteoclasts treated with LPS or IFN-gamma [13].

Physical interactions of NOS2A

• Nitric oxide, which is produced in metastases by three different NOS isozymes is capable of antagonizing the binding of FAK to matrix integrins [26].
• In RNA binding studies TIAR displayed high affinity binding to the human iNOS 3'-UTR sequence [27].
• Mapping of the binding site revealed KSRP interacting with the most 3'-located AU-rich element (ARE) of the human iNOS mRNA [28].
• Interferon gamma (IFN-gamma) interacts synergistically with bacterial lipopolysaccharide (LPS) to induce transcription of iNOS, the isoform of nitric oxide synthase whose activity is independent of elevated Ca2+ and exogenous calmodulin [29].
• In conclusion, using two cell systems, we demonstrated that the ETB receptor is functionally coupled to NOS and coordinates the generation of NO via a tyrosine kinase-dependent and a calcium/calmodulin-dependent pathway [30].

Enzymatic interactions of NOS2A

• NOS catalyzes the NADPH- and oxygen-dependent oxygenation of L-arginine to NO plus L-citrulline in a reaction that requires at least six cofactors including NADPH, FAD, FMN, tetrahydrobiopterin, heme, and calmodulin [31].

Co-localisations of NOS2A

• Despite their apparent promiscuity, the NOS isoforms support specific signaling because of their subcellular compartmentation with colocalized effectors and limited diffusibility of NO in muscle cells. eNOS and nNOS sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart [32].
• Nitrotyrosine was found in the same distribution as that of iNOS and was colocalized with Cox-2 in macrophages [33].
• Immunocytochemical double labeling revealed that both anti-iNOS immunoreactivity and anti-IL-1beta immunoreactivity colocalized with glial fibrillary acidic protein immunoreactivity in GBM [34].
• Abeta colocalized with iNOS-expressing macrophages that were often surrounded by platelets [35].

Regulatory relationships of NOS2A

• Interestingly, Stat 1 is repressive to basal and stimulated iNOS mRNA expression in 2fTGH human fibroblasts, which are refractory to iNOS induction [36].
• Taken together, these results suggest that cav-1 promotes iNOS presence in detergent-insoluble membrane fractions and degradation there via the proteasome pathway [37].
• Nitric-oxide synthase (NOS) reductase domain models suggest a new control element in endothelial NOS that attenuates calmodulin-dependent activity [38].
• Mutation of both these sites abrogated the KLF6-induced enhancement of the 0.63-kb iNOS promoter activity [39].
• Finally, ET-1 is able to influence its own as well as NOS isoform expression in normal and PE trophoblastic cultured cells [40].

Other interactions of NOS2A

• The release of NO and PGs by the inducible isoforms of NOS and COX has been associated with the pathological roles of these mediators in disease states as evidenced by the use of selective inhibitors [41].
• Thus, eNOS and iNOS proteins are differentially expressed in healthy human liver, and this expression is significantly altered in cirrhotic liver disorders [42].
• Ectopic expression of cav-1 in both cell lines correlated with significantly decreased iNOS activity and protein levels [37].
• In human microglia, cytokines and LPS failed to induce NOS II expression, while the same stimuli readily induced TNF-alpha expression [43].
• The inducing signals for astrocyte NOS II mRNA expression were in the order IL-1beta + IFN-gamma > IL-1beta + TNF-alpha > IL-1beta [43].

Analytical, diagnostic and therapeutic context of NOS2A

• Patients and ethnically matched controls (n=251) were genotyped by PCR based techniques for a multiallelic (CCTTT)n and for the biallelic TAAA repeat in the promoter region of the NOS2A gene [3].
• This pattern of distribution of eNOS and iNOS in normal liver was confirmed by in situ hybridization [42].
• Northern blot analysis with hep-NOS cDNA reveals a 4.5-kb mRNA in both human hepatocytes and aortic smooth muscle cells following stimulation with LPS and cytokines [25].
• Cell culture with epidermal growth factor, a principal regulator of epithelial cell function, decreased inducible NOS activity by posttranscriptional action but did not affect constitutive NOS activity [44].
• Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study [45].

References