Disease relevance of NOS1

• Loss of NOS1 expression in high-grade renal cell carcinoma associated with a shift of NO signalling [1].
• CONCLUSION: Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Americans is warranted [2].
• The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FENO in adults with asthma and cystic fibrosis, was associated with the raised FENO in healthy atopic children [3].
• Western blot analysis showed that the n-NOS expressed in neuroblastoma cells was a 160-kDa protein reacted with anti-n-NOS antibody [4].
• In patients with COPD, neuronal NOS expression correlated negatively with the degree of the airway obstruction (%FEV1 predicted) [5].

Psychiatry related information on NOS1

• The present study examines the existence and location of the constitutive isoform eNOS (endothelial NO synthase) accompanying the already substantiated neurogenic NOS (nNOS) in the human corpus cavernosum of men with and without erectile dysfunction [6].
• The expression of neuronal nitric oxide (nNOS) and inducible nitric oxide (iNOS) as isoforms of the nitric oxide synthase (NOS) as well as nitrotyrosine as an end product of protein nitration was analyzed in sections of temporal cortex taken from postmortem brains of patients with Alzheimer's disease (AD) [7].
• We also show that the expression of the anti-NOS gene, which functions as a negative regulator of nNOS expression, is downregulated in the CGC by training at 4 h after conditioning, during the critical period of NO requirement [8].
• Importantly, our results establish that the expression of nNOS gene is essential for normal feeding behavior [9].

High impact information on NOS1

• 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 [10].
• A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization [11].
• Neuronal nitric oxide synthase (nNOS) is concentrated at synaptic junctions in brain and motor endplates in skeletal muscle [12].
• OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice [13].
• New insights into nNOS regulation of vascular homeostasis [14].

Chemical compound and disease context of NOS1

• Pre-injury treatment with 7-nitroindazole, which probably inhibits this immediate increase in NO by neuronal NOS, is effective in improving neurological outcome in some models of traumatic brain injury (TBI) [15].
• In this issue of the JCI, Ward et al. demonstrate that changes in O2 concentration have effects on neuronal NOS enzymatic activity and gene expression that contribute to vascular homeostasis under conditions of acute and chronic hypoxia (see the related article beginning on page 3128) [14].
• METHODS AND RESULTS: We constructed a recombinant adenovirus, Ad.nNOS, that expresses the neuronal isoform of NOS (nNOS) and used it for in vivo endovascular gene transfer to carotid arteries (CA) from normal and cholesterol-fed rabbits [16].
• In a neuronal NO synthase (nNOS) overexpressing neuroblastoma cell line exposed to the differentiative action of retinoic acid, NO slowed down proliferation and accelerated differentiation towards a neuronal phenotype [17].
• Using NADPH diaphorase as a marker for neuronal NOS, deficiency of the nitrergic innervation has been shown in isolated tissue from patients with infantile hypertrophic pyloric stenosis, achalasia and Hirschsprung's disease, suggesting that a lack of NO release might be involved in these disorders [18].

Biological context of NOS1

• We investigated the association between asthma traits and genetic polymorphisms in neuronal NO synthase (NOS1) and endothelial NO synthase (NOS3) in Chinese children [19].
• NOS1 C5266T and NOS3 G894T were genotyped by restriction fragment length polymorphism, and (AAT)n polymorphism in intron 20 of NOS1 was determined by GeneScan analysis [19].
• Intragenic microsatellite variants of NOS1 were significantly associated with asthma [odds ratio (OR) = 2.08, 95% CI: 1.20-3.57 (95% CI), P = 0.008 (Pc = 0.048)], but not with IgE levels [20].
• This review will focus on the nitric oxide synthase gene family and recent progress on molecular genetic analysis of NOS1, NOS2 and NOS3 genes [21].
• Our results suggest that NOS1 and STAT6 are asthma-susceptibility genes and that chromosome region 12q24.23-q24.33 contains other susceptibility gene(s) [22].

Anatomical context of NOS1

• Also, BEC increased contractility in isolated myocytes from WT and NOS3 but not NOS1 knockout mice [23].
• Moreover, epithelial cells expressing NOS1 also express soluble guanylyl cyclase, indicating that these cells possess the machinery for autocrine/paracrine effect of nitric oxide [24].
• NO also participates in mitochondrial respiration, the process that fuels EC coupling, and either NOS1 or 3 resides within cardiac mitochondria [25].
• Patterns among tissue extracts were strikingly different, with ECNOS mRNA being most abundant in aorta, heart, lung, kidney, adrenal gland, spinal cord, and urogenital tissues and bNOS mRNA most prominent in brain regions, intestine, stomach, spinal cord, adrenal gland, and aorta [26].
• Expression of the n-NOS mRNA was also detected in another neuroblastoma cell line in a subsequent reverse transcriptase polymerase chain reaction (RT-PCR) study, but no n-NOS mRNA expression was observed in the other four neuroblastoma cell lines or in the glioblastoma cell lines [4].

Associations of NOS1 with chemical compounds

• Both the Arg inhibitors N-hydroxy-nor-l-arginine and BEC dose-dependently increased basal contractility in rat myocytes, which was inhibited by both nonspecific and NOS1-specific NOS inhibitors N(G)-nitro-l-arginine methyl ester and S-methyl-l-thiocitrulline, respectively [23].
• RESULTS: All these techniques led to consistent results showing that epithelial cells of most tubules along the human nephron exhibit functional NOS1, with a corticomedullary gradient observed both at the protein and mRNA levels [24].
• Finally, the staining pattern of protein tyrosine nitration, assessed by immunohistochemistry, parallelled that of NOS1 expression in normal renal parenchyma and benign tumours, supporting the concept that protein nitration was accounted for by NOS1 activity [1].
• A higher intensity expression of NOS1 and NOS3 was recorded in the tissues around titanium, whereas, on the contrary, a lower intensity of expression was found in the tissues around zirconium oxide specimens [27].
• Although several mechanisms are proposed to explain the reduction of cNOS activity, reduced substrate availability, caused by a combination of increased arginase activity and decreased cellular uptake of L-arginine, appears to play a key role [28].

Physical interactions of NOS1

• In the ischemic and failing myocardium, iNOS expression is induced and further contributes to attenuate the inotropic effect of catecholamines, as does eNOS coupled to overexpressed beta3-adrenoceptors. nNOS expression also increases in the aging and ischemic heart, but its role (compensatory or deleterious) remains to be defined [29].
• A chimera consisting of the nNOS heme domain and FMN binding subdomain and the CYPOR FAD binding subdomain catalyzed significantly increased rates of cytochrome c reduction in the absence of CaM and of NO synthesis in its presence [30].
• The effect of HSP90 is mediated by the enhancement of CaM binding to nNOS [31].

Enzymatic interactions of NOS1

• CaM-K Ialpha and CaM-K IV failed to phosphorylate nNOS at Ser(847) in transfected cells [32].

Co-localisations of NOS1

• Expression of nNOS in these neurons was highly co-localized with p21ras and p16INK4a [33].

Regulatory relationships of NOS1

• Furthermore, NO produced from newly induced neuronal NOS was reported to induce expression of thioredoxin and several other genes for preconditioning-induced neuroprotection [34].
• We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain [23].
• Endothelial NOS was evenly expressed in all groups while neuronal NOS was undetectable [35].
• Thus, we attempted to study whether or not a decrease of dystrophin expression would induce a modification in nNOS expression in cultured human neurons [36].
• NMMA blocked completely the somatostatin stimulated increase of cGMP levels and nNOS was detected in rat retina. cGMP immunoreactivity was observed primarily in bipolar cells only of nitroprusside-treated retinas [37].

Other interactions of NOS1

• Both growth factor-independent (HMC-1) and -dependent (LAD 2) MC lines showed predominant nuclear eNOS protein localization, with weaker cytoplasmic expression. nNOS showed exclusive cytoplasmic localization in HMC-1 [38].
• Immunoblotting analysis using frontal tissue homogenates at 15, 28, 40 weeks of gestation and 18 months of age revealed single band corresponding to SOD1 molecular weight, observed at all stages examined; a single band compatible with the nNOS molecular mass was detected only at the 28th week of gestation [39].
• The NOS1 intron 2 GT repeat and STAT6 exon 1 GT repeat were associated with asthma [22].
• The carbachol-induced corticosterone response was significantly increased by pretreatment with nNOS inhibitor L-NNA and was considerably reduced by indomethacin, a general COX inhibitor [40].
• Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPHD1-1/2 (EDN-1) were genotyped in the sample [2].

Analytical, diagnostic and therapeutic context of NOS1

• NOS1 expression and activity were found to be downregulated, correlating with the tumour grade, as shown by immunohistochemistry, quantitative RT-PCR analysis, and histochemical detection of the NADPH-diaphorase activity of nitric oxide synthases (NOS) [1].
• By Western immunoblot analysis, neuronal NOS or iNOS was not detected [41].
• Specific immunofluorescence for neuronal NOS (nNOS, or isoform I) was not observed in any sections [42].
• Tissue distribution of ECNOS mRNA (4.4 kb) and bNOS mRNA (9.5 kb) in the rat was detected by Northern blotting [26].
• After 2 hr of reperfusion, the nNOS protein in the NO group was significantly higher than that in the placebo group (P <0.05) [43].

1. Loss of NOS1 expression in high-grade renal cell carcinoma associated with a shift of NO signalling. Renaudin, K., Denis, M.G., Karam, G., Vallette, G., Buzelin, F., Laboisse, C.L., Jarry, A. Br. J. Cancer (2004)
2. Genetic analysis of nitric oxide and endothelin in end-stage renal disease. Freedman, B.I., Yu, H., Anderson, P.J., Roh, B.H., Rich, S.S., Bowden, D.W. Nephrol. Dial. Transplant. (2000)
3. NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children. Ali, M., Khoo, S.K., Turner, S., Stick, S., Le Souëf, P., Franklin, P. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. (2003)
4. Expression of two types of nitric oxide synthase mRNA in human neuroblastoma cell lines. Fujisawa, H., Ogura, T., Kurashima, Y., Yokoyama, T., Yamashita, J., Esumi, H. J. Neurochem. (1994)
5. Nitric oxide synthases and protein oxidation in the quadriceps femoris of patients with chronic obstructive pulmonary disease. Barreiro, E., Gea, J., Corominas, J.M., Hussain, S.N. Am. J. Respir. Cell Mol. Biol. (2003)
6. Evidence for the involvement of endothelial nitric oxide synthase from smooth muscle cells in the erectile function of the human corpus cavernosum. Bloch, W., Klotz, T., Sedlaczek, P., Zumbé, J., Engelmann, U., Addicks, K. Urol. Res. (1998)
7. Expression of nitric oxide system in clinically evaluated cases of Alzheimer's disease. Fernández-Vizarra, P., Fernández, A.P., Castro-Blanco, S., Encinas, J.M., Serrano, J., Bentura, M.L., Muñoz, P., Martínez-Murillo, R., Rodrigo, J. Neurobiol. Dis. (2004)
8. Timed and targeted differential regulation of nitric oxide synthase (NOS) and anti-NOS genes by reward conditioning leading to long-term memory formation. Korneev, S.A., Straub, V., Kemenes, I., Korneeva, E.I., Ott, S.R., Benjamin, P.R., O'Shea, M. J. Neurosci. (2005)
9. Suppression of nitric oxide (NO)-dependent behavior by double-stranded RNA-mediated silencing of a neuronal NO synthase gene. Korneev, S.A., Kemenes, I., Straub, V., Staras, K., Korneeva, E.I., Kemenes, G., Benjamin, P.R., O'Shea, M. J. Neurosci. (2002)
10. Nitric oxide in health and disease of the respiratory system. Ricciardolo, F.L., Sterk, P.J., Gaston, B., Folkerts, G. Physiol. Rev. (2004)
11. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Arking, D.E., Pfeufer, A., Post, W., Kao, W.H., Newton-Cheh, C., Ikeda, M., West, K., Kashuk, C., Akyol, M., Perz, S., Jalilzadeh, S., Illig, T., Gieger, C., Guo, C.Y., Larson, M.G., Wichmann, H.E., Marbán, E., O'Donnell, C.J., Hirschhorn, J.N., Kääb, S., Spooner, P.M., Meitinger, T., Chakravarti, A. Nat. Genet. (2006)
12. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Brenman, J.E., Chao, D.S., Gee, S.H., McGee, A.W., Craven, S.E., Santillano, D.R., Wu, Z., Huang, F., Xia, H., Peters, M.F., Froehner, S.C., Bredt, D.S. Cell (1996)
13. Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma. De Sanctis, G.T., MacLean, J.A., Hamada, K., Mehta, S., Scott, J.A., Jiao, A., Yandava, C.N., Kobzik, L., Wolyniec, W.W., Fabian, A.J., Venugopal, C.S., Grasemann, H., Huang, P.L., Drazen, J.M. J. Exp. Med. (1999)
14. New insights into nNOS regulation of vascular homeostasis. Semenza, G.L. J. Clin. Invest. (2005)
15. Nitric oxide in traumatic brain injury. Cherian, L., Hlatky, R., Robertson, C.S. Brain Pathol. (2004)
16. In vivo gene transfer of nitric oxide synthase enhances vasomotor function in carotid arteries from normal and cholesterol-Fed rabbits. Channon, K.M., Qian, H., Neplioueva, V., Blazing, M.A., Olmez, E., Shetty, G.A., Youngblood, S.A., Pawloski, J., McMahon, T., Stamler, J.S., George, S.E. Circulation (1998)
17. Nitric oxide negatively regulates proliferation and promotes neuronal differentiation through N-Myc downregulation. Ciani, E., Severi, S., Contestabile, A., Bartesaghi, R., Contestabile, A. J. Cell. Sci. (2004)
18. Nitric oxide in the peripheral nervous system. Lefebvre, R.A. Ann. Med. (1995)
19. Nitric oxide synthase polymorphisms and asthma phenotypes in Chinese children. Leung, T.F., Liu, E.K., Tang, N.L., Ko, F.W., Li, C.Y., Lam, C.W., Wong, G.W. Clin. Exp. Allergy (2005)
20. Variants of NOS1, NOS2, and NOS3 genes in asthmatics. Gao, P.S., Kawada, H., Kasamatsu, T., Mao, X.Q., Roberts, M.H., Miyamoto, Y., Yoshimura, M., Saitoh, Y., Yasue, H., Nakao, K., Adra, C.N., Kun, J.F., Moro-oka, S., Inoko, H., Ho, L.P., Shirakawa, T., Hopkin, J.M. Biochem. Biophys. Res. Commun. (2000)
21. Nitric oxide: from a mysterious labile factor to the molecule of the Nobel Prize. Recent progress in nitric oxide research. Xu, W.M., Liu, L.Z. Cell Res. (1998)
22. Linkage and association of childhood asthma with the chromosome 12 genes. Shao, C., Suzuki, Y., Kamada, F., Kanno, K., Tamari, M., Hasegawa, K., Aoki, Y., Kure, S., Yang, X., Endo, H., Takayanagi, R., Nakazawa, C., Morikawa, T., Morikawa, M., Miyabayashi, S., Chiba, Y., Karahashi, M., Saito, S., Tamura, G., Shirakawa, T., Matsubara, Y. J. Hum. Genet. (2004)
23. Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism. Steppan, J., Ryoo, S., Schuleri, K.H., Gregg, C., Hasan, R.K., White, A.R., Bugaj, L.J., Khan, M., Santhanam, L., Nyhan, D., Shoukas, A.A., Hare, J.M., Berkowitz, D.E. Proc. Natl. Acad. Sci. U.S.A. (2006)
24. Expression of NOS1 and soluble guanylyl cyclase by human kidney epithelial cells: morphological evidence for an autocrine/paracrine action of nitric oxide. Jarry, A., Renaudin, K., Denis, M.G., Robard, M., Buffin-Meyer, B., Karam, G., Buzelin, F., Paris, H., Laboisse, C.L., Vallette, G. Kidney Int. (2003)
25. Nitric oxide and excitation-contraction coupling. Hare, J.M. J. Mol. Cell. Cardiol. (2003)
26. Genomic analysis and expression patterns reveal distinct genes for endothelial and brain nitric oxide synthase. Sessa, W.C., Harrison, J.K., Luthin, D.R., Pollock, J.S., Lynch, K.R. Hypertension (1993)
27. Inflammatory infiltrate, microvessel density, nitric oxide synthase expression, vascular endothelial growth factor expression, and proliferative activity in peri-implant soft tissues around titanium and zirconium oxide healing caps. Degidi, M., Artese, L., Scarano, A., Perrotti, V., Gehrke, P., Piattelli, A. J. Periodontol. (2006)
28. Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Meurs, H., Maarsingh, H., Zaagsma, J. Trends Pharmacol. Sci. (2003)
29. Nitric oxide "at heart": emerging paradigms after a decade. Pelat, M., Massion, P.B., Balligand, J.L. Archives des maladies du coeur et des vaisseaux. (2005)
30. Chimeric enzymes of cytochrome P450 oxidoreductase and neuronal nitric-oxide synthase reductase domain reveal structural and functional differences. Roman, L.J., McLain, J., Masters, B.S. J. Biol. Chem. (2003)
31. Determination of the enhancing action of HSP90 on neuronal nitric oxide synthase by EPR spectroscopy. Song, Y., Zweier, J.L., Xia, Y. Am. J. Physiol., Cell Physiol. (2001)
32. Post-synaptic density-95 promotes calcium/calmodulin-dependent protein kinase II-mediated Ser847 phosphorylation of neuronal nitric oxide synthase. Watanabe, Y., Song, T., Sugimoto, K., Horii, M., Araki, N., Tokumitsu, H., Tezuka, T., Yamamoto, T., Tokuda, M. Biochem. J. (2003)
33. Aberrant expression of nNOS in pyramidal neurons in Alzheimer's disease is highly co-localized with p21ras and p16INK4a. Lüth, H.J., Holzer, M., Gertz, H.J., Arendt, T. Brain Res. (2000)
34. Thioredoxin-related regulation of NO/NOS activities. Shao, L.E., Tanaka, T., Gribi, R., Yu, J. Ann. N. Y. Acad. Sci. (2002)
35. Expression of nitric oxide synthases and effects of L-arginine and L-NMMA on nitric oxide production and fluid transport in collagenous colitis. Perner, A., Andresen, L., Normark, M., Fischer-Hansen, B., Sørensen, S., Eugen-Olsen, J., Rask-Madsen, J. Gut (2001)
36. Dystrophin antisense oligonucleotides decrease expression of nNOS in human neurons. Sogos, V., Reali, C., Fanni, V., Curto, M., Gremo, F. Brain Res. Mol. Brain Res. (2003)
37. Somatostatin receptors (sst2) regulate cGMP production in rat retina. Mastrodimou, N., Kiagiadaki, F., Hodjarova, M., Karagianni, E., Thermos, K. Regul. Pept. (2006)
38. Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production. Gilchrist, M., McCauley, S.D., Befus, A.D. Blood (2004)
39. Temporospatial relationship between the expressions of superoxide dismutase and nitric oxide synthase in the developing human brain: immunohistochemical and immunoblotting analyses. Takikawa, M., Kato, S., Esumi, H., Kurashima, Y., Hirano, A., Asayama, K., Nakashima, K., Ohama, E. Acta Neuropathol. (2001)
40. The involvement of nitric oxide and prostaglandins in the cholinergic stimulation of hypothalamie-pituitary-adrenal response during crowding stress. Bugajski, A.J., Gadek-Michalska, A., Bugajski, J. J. Physiol. Pharmacol. (2006)
41. Endometrial and myometrial expression of nitric oxide synthase isoforms in pre- and postmenopausal women. Khorram, O., Garthwaite, M., Magness, R.R. J. Clin. Endocrinol. Metab. (1999)
42. Induction of nitric oxide synthase in the neointima induced by a periarterial collar in rabbits. Arthur, J.F., Yin, Z.L., Young, H.M., Dusting, G.J. Arterioscler. Thromb. Vasc. Biol. (1997)
43. Increased expression of nitric oxide synthase in human lung transplants after nitric oxide inhalation. Cardella, J.A., Keshavjee, S.H., Bai, X.H., Yeoh, J.S., Granton, J.T., Meade, M.O., Matte-Martyn, A., Waddell, T.K., Liu, M. Transplantation (2004)