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Gene Review

NOS3  -  nitric oxide synthase 3 (endothelial cell)

Homo sapiens

Synonyms: Constitutive NOS, EC-NOS, ECNOS, Endothelial NOS, NOS type III, ...
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Disease relevance of NOS3

  • Furthermore, we show that NOS3 promotes thrombosis in vivo [1].
  • Polymorphisms of NOS3, the gene that codes for endothelial nitric oxide synthase, have been associated with essential hypertension [2].
  • CONCLUSIONS: This study provides evidence of an association between the NOS3 gene and subjects with glaucoma who have a history of migraine [3].
  • We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low [4].
  • Sepsis is associated with reciprocal expressional modifications of constitutive nitric oxide synthase (NOS) in human skeletal muscle: down-regulation of NOS1 and up-regulation of NOS3 [5].
  • The relation between several NOS3 polymorphisms and the high tension variant of primary open-angle glaucoma is modified by postmenopausal hormone use. [6]

Psychiatry related information on NOS3

  • The distribution of the Glu298Asp polymorphism in NOS3 gene was determined in 405 Italian patients with "probable" Alzheimer's disease (AD) compared with 253 age-matched controls [7].
  • 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 [8].
  • 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 [9].
  • NOS3 G894T genotype was not significantly associated, either independently or interactively with habitual physical activity (PA) level, with SBP, Q, TPR, or a-vO2 diff during submaximal or maximal exercise [10].
  • We compared eNOS expression in gentamicin-treated and non-treated guinea pigs in the second turn of the cochlea, an area corresponding to speech perception in humans [11].

High impact information on NOS3

  • The recent colocalization of the cationic amino acid transporter CAT-1 (system y(+)), nitric oxide synthase (eNOS), and caveolin-1 in endothelial plasmalemmal caveolae provides a novel mechanism for the regulation of NO production by L-arginine delivery and circulating hormones such insulin and 17beta-estradiol [12].
  • These data refute the idea that NOS3 is obligatory for the normal autonomic control of cardiac muscle function [13].
  • Here we demonstrate that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production [14].
  • Inhibition of the phosphatidylinositol-3-OH kinase/Akt pathway or mutation of the Akt site on eNOS protein (at serine 1177) attenuates the serine phosphorylation and prevents the activation of eNOS [14].
  • Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is a fundamental determinant of cardiovascular homesotasis: it regulates systemic blood pressure, vascular remodelling and angiogenesis [14].

Chemical compound and disease context of NOS3


Biological context of NOS3

  • RESULTS: In contrast to cells of other genotypes, endothelial cells of the (-786)C/C genotype did not reveal an increase in NOS3 expression upon exposure to IL-10, and the cytokine failed to suppress IL-12 expression upon stimulation of CD40 [20].
  • This may be explained by the IL-10 insensitivity of the C-type NOS3 gene promoter and the resulting failure to subdue CD40-mediated proinflammatory gene expression [20].
  • Interestingly, a promoter variant of the NOS3 gene, the (-786)C variant, is insensitive to shear stress, and individuals homozygous for this single-nucleotide polymorphism (SNP) have an increased risk of developing coronary artery disease [20].
  • These results pave the way for studies looking for the influence of NOS3 on blood pressure in high-risk subsets such as diabetic or hypertensive patients [2].
  • CONCLUSION: We show for the first time a highly significant association of ambulatory blood pressure with NOS3 haplotypes in well-characterized white individuals from Flanders [2].

Anatomical context of NOS3

  • NOS III (NOS3, ecNOS) is expressed mainly in endothelial cells [21].
  • The human alveolar type II epithelium-like cell line A549 expresses nitric oxide synthase type 2 (NOS2), but not NOS3, and produces nitric oxide (NO) upon appropriate stimulation [22].
  • OBJECTIVE: To study the expression (mRNA and protein) and activity of the constitutive isoforms of nitric oxide synthase (NOS1 and NOS3) in a skeletal muscle of septic patients [5].
  • However, relatively little is known regarding the NOS2 and NOS3 expression of type II human alveolar epithelial cells (AEC II) in primary culture [22].
  • Consistent with the targeting of overexpressed NOS3 to caveolae in the vicinity of cholinergic and adrenergic receptors, these studies have highlighted the importance of NOS3-derived NO in the modulation of autonomic cardiac stimulation [23].

Associations of NOS3 with chemical compounds


Physical interactions of NOS3

  • Loss of the DNA binding domain did not change E2 activation of Src or erk, but ligand-induced PI3 kinase-ERalpha binding and eNOS phosphorylation did not occur [26].
  • We identified four consensus sequences for Stat3 binding (SIE) in the eNOS promoter at positions -1520, -1024, -840, and -540 [27].
  • BACKGROUND: Estrogens can upregulate endothelial nitric oxide synthase (eNOS) in human endothelial cells by increasing eNOS promoter activity and enhancing the binding activity of the transcription factor Sp1 [28].
  • In this study, we examined whether the modulation of the stoichiometry of the caveolin/eNOS complex in EC lining tumor blood vessels could affect the tumor vasculature and consecutively tumor growth [29].
  • Regulation of the endothelial isoform of nitric oxide synthase (eNOS) appears to be much more complex in comparison to that of other NOS isoforms [30].

Enzymatic interactions of NOS3

  • As expected there was only a weak colocalization between eNOS phosphorylated at Ser-1177 and caveolin-1 [31].
  • Besides acting as an allosteric enhancer, Hsp90 was shown to serve as a module recruiting Akt to phosphorylate the serine 1179/1177 (bovine/human) residue of eNOS [32].
  • AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and activate eNOS at Ser-1177 in vitro, yet the function of AMPK in endothelium is poorly characterized [33].
  • Despite the narrowing of arterial diameter and reduced expression of eNOS, expressions of phosphorylated protein kinase B (Akt) and phosphorylated eNOS were significantly increased in spastic arteries [34].

Co-localisations of NOS3

  • Endothelial NOS protein co-localized to areas that showed positive NADPH diaphorase activity [35].
  • However, within 10 min following addition of TRAIL, nearly all the cells showed an increased cytoplasm localization of eNOS which appeared co-localized with the Golgi apparatus at a higher extent than in unstimulated cells [36].
  • NOSTRIN colocalized extensively with eNOS at the plasma membrane of confluent human umbilical venous endothelial cells and in punctate cytosolic structures of CHO-eNOS cells [37].
  • Stimulatory phosphorylation of eNOS (Ser1177) was also reduced in moderately hyperglycemic diabetic rats. eNOS colocalized and interacted with CAV-1 in endothelial cells throughout the renal vascular tree both in control and moderately hyperglycemic diabetic rats [38].

Regulatory relationships of NOS3


Other interactions of NOS3

  • Thus, eNOS and iNOS proteins are differentially expressed in healthy human liver, and this expression is significantly altered in cirrhotic liver disorders [44].
  • ER46 more efficiently modulates membrane-initiated estrogen actions, including eNOS activation, than full-length ER66 [39].
  • Here we identify the 110-kDa caveolin-binding protein striatin as the molecular anchor that localizes ERalpha to the membrane and organizes the ERalpha-eNOS membrane signaling complex [45].
  • 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 [46].
  • Taxotere prevented the VEGF-induced phosphorylation of focal adhesion kinase, Akt, and endothelial nitric oxide synthase (eNOS), all of which are Hsp90 client proteins [47].

Analytical, diagnostic and therapeutic context of NOS3




  1. Stimulatory roles of nitric-oxide synthase 3 and guanylyl cyclase in platelet activation. Marjanovic, J.A., Li, Z., Stojanovic, A., Du, X. J. Biol. Chem. (2005) [Pubmed]
  2. Influence of the endothelial nitric oxide synthase gene on conventional and ambulatory blood pressure: sib-pair analysis and haplotype study. Persu, A., Vinck, W.J., El Khattabi, O., Janssen, R.G., Paulussen, A.D., Devuyst, O., Vlietinck, R., Fagard, R.H. J. Hypertens. (2005) [Pubmed]
  3. Evidence for association of endothelial nitric oxide synthase gene in subjects with glaucoma and a history of migraine. Logan, J.F., Chakravarthy, U., Hughes, A.E., Patterson, C.C., Jackson, J.A., Rankin, S.J. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  4. The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine. Brown, K.S., Kluijtmans, L.A., Young, I.S., Murray, L., McMaster, D., Woodside, J.V., Yarnell, J.W., Boreham, C.A., McNulty, H., Strain, J.J., McPartlin, J., Scott, J.M., Mitchell, L.E., Whitehead, A.S. Atherosclerosis (2004) [Pubmed]
  5. Sepsis is associated with reciprocal expressional modifications of constitutive nitric oxide synthase (NOS) in human skeletal muscle: down-regulation of NOS1 and up-regulation of NOS3. Lanone, S., Mebazaa, A., Heymes, C., Valleur, P., Mechighel, P., Payen, D., Aubier, M., Boczkowski, J. Crit. Care Med. (2001) [Pubmed]
  6. Endothelial nitric oxide synthase gene variants and primary open-angle glaucoma: interactions with sex and postmenopausal hormone use. Kang, J.H., Wiggs, J.L., Rosner, B.A., Hankinson, S.E., Abdrabou, W., Fan, B.J., Haines, J., Pasquale, L.R. Invest. Ophthalmol. Vis. Sci. (2010) [Pubmed]
  7. Influence of the Glu298Asp polymorphism of NOS3 on age at onset and homocysteine levels in AD patients. Guidi, I., Galimberti, D., Venturelli, E., Lovati, C., Del Bo, R., Fenoglio, C., Gatti, A., Dominici, R., Galbiati, S., Virgilio, R., Pomati, S., Comi, G.P., Mariani, C., Forloni, G., Bresolin, N., Scarpini, E. Neurobiol. Aging (2005) [Pubmed]
  8. Nitric oxide synthase gene polymorphisms in Alzheimer's disease and dementia with Lewy bodies. Singleton, A.B., Gibson, A.M., McKeith, I.G., Ballard, C.G., Edwardson, J.A., Morris, C.M. Neurosci. Lett. (2001) [Pubmed]
  9. 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) [Pubmed]
  10. NOS3 gene polymorphisms and exercise hemodynamics in postmenopausal women. Hand, B.D., McCole, S.D., Brown, M.D., Park, J.J., Ferrell, R.E., Huberty, A., Douglass, L.W., Hagberg, J.M. International journal of sports medicine (2006) [Pubmed]
  11. Endothelial nitric oxide synthase upregulation in the cochlea of the guinea pig after intratympanic gentamicin injection. Heinrich, U.R., Selivanova, O., Brieger, J., Mann, W.J. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. (2006) [Pubmed]
  12. Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Mann, G.E., Yudilevich, D.L., Sobrevia, L. Physiol. Rev. (2003) [Pubmed]
  13. Muscarinic and beta-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. Vandecasteele, G., Eschenhagen, T., Scholz, H., Stein, B., Verde, I., Fischmeister, R. Nat. Med. (1999) [Pubmed]
  14. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., Zeiher, A.M. Nature (1999) [Pubmed]
  15. Tyrosine phosphorylation of NOS3 in a breast cancer cell line and Src-transformed cells. Takenouchi, Y., Oo, M.L., Senga, T., Watanabe, Y., Machida, K., Miyazaki, K., Nimura, Y., Hamaguchi, M. Oncol. Rep. (2004) [Pubmed]
  16. Subunit interactions of endothelial nitric-oxide synthase. Comparisons to the neuronal and inducible nitric-oxide synthase isoforms. Venema, R.C., Ju, H., Zou, R., Ryan, J.W., Venema, V.J. J. Biol. Chem. (1997) [Pubmed]
  17. The Isoflavone Equol Mediates Rapid Vascular Relaxation: Ca2+-INDEPENDENT ACTIVATION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE/Hsp90 INVOLVING ERK1/2 AND Akt PHOSPHORYLATION IN HUMAN ENDOTHELIAL CELL. Joy, S., Siow, R.C., Rowlands, D.J., Becker, M., Wyatt, A.W., Aaronson, P.I., Coen, C.W., Kallo, I., Jacob, R., Mann, G.E. J. Biol. Chem. (2006) [Pubmed]
  18. Expression of endothelial (type III) nitric oxide synthase in cytotrophoblastic cell lines: regulation by hypoxia and inflammatory cytokines. Kiss, H., Schneeberger, C., Tschugguel, W., Lass, H., Huber, J.C., Husslein, P., Knöfler, M. Placenta (1998) [Pubmed]
  19. Regulation of the nitric oxide system in human adipose tissue. Engeli, S., Janke, J., Gorzelniak, K., Böhnke, J., Ghose, N., Lindschau, C., Luft, F.C., Sharma, A.M. J. Lipid Res. (2004) [Pubmed]
  20. The (-786)C/T single-nucleotide polymorphism in the promoter of the gene for endothelial nitric oxide synthase: Insensitivity to physiologic stimuli as a risk factor for rheumatoid arthritis. Melchers, I., Blaschke, S., Hecker, M., Cattaruzza, M. Arthritis Rheum. (2006) [Pubmed]
  21. Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). Förstermann, U., Boissel, J.P., Kleinert, H. FASEB J. (1998) [Pubmed]
  22. Pattern of NOS2 and NOS3 mRNA expression in human A549 cells and primary cultured AEC II. Pechkovsky, D.V., Zissel, G., Goldmann, T., Einhaus, M., Taube, C., Magnussen, H., Schlaak, M., Müller-Quernheim, J. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  23. Cardiomyocyte-specific overexpression of nitric oxide synthase 3: impact on left ventricular function and myocardial infarction. Bloch, K.D., Janssens, S. Trends Cardiovasc. Med. (2005) [Pubmed]
  24. Association of endothelial nitric oxide synthase genotypes with bone mineral density, bone loss, hip structure, and risk of fracture in older women: the SOF study. Taylor, B.C., Schreiner, P.J., Zmuda, J.M., Li, J., Moffett, S.P., Beck, T.J., Cummings, S.R., Lee, J.M., Walker, K., Ensrud, K.E. Bone (2006) [Pubmed]
  25. Total homocysteine is not a determinant of arterial pulse wave velocity in young healthy adults. Woodside, J.V., McMahon, R., Gallagher, A.M., Cran, G.W., Boreham, C.A., Murray, L.J., Strain, J.J., McNulty, H., Robson, P.J., Brown, K.S., Whitehead, A.S., Savage, M., Young, I.S. Atherosclerosis (2004) [Pubmed]
  26. Dissecting the basis of nongenomic activation of endothelial nitric oxide synthase by estradiol: role of ERalpha domains with known nuclear functions. Chambliss, K.L., Simon, L., Yuhanna, I.S., Mineo, C., Shaul, P.W. Mol. Endocrinol. (2005) [Pubmed]
  27. Stat3 Mediates Interelukin-6 Inhibition of Human Endothelial Nitric-oxide Synthase Expression. Saura, M., Zaragoza, C., Bao, C., Herranz, B., Rodriguez-Puyol, M., Lowenstein, C.J. J. Biol. Chem. (2006) [Pubmed]
  28. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Wallerath, T., Deckert, G., Ternes, T., Anderson, H., Li, H., Witte, K., Förstermann, U. Circulation (2002) [Pubmed]
  29. Antitumor effects of in vivo caveolin gene delivery are associated with the inhibition of the proangiogenic and vasodilatory effects of nitric oxide. Brouet, A., DeWever, J., Martinive, P., Havaux, X., Bouzin, C., Sonveaux, P., Feron, O. FASEB J. (2005) [Pubmed]
  30. Another activation switch for endothelial nitric oxide synthase: why does it have to be so complicated? Marletta, M.A. Trends Biochem. Sci. (2001) [Pubmed]
  31. Phospho-eNOS Ser-114 in human mesenchymal stem cells: constitutive phosphorylation, nuclear localization and upregulation during mitosis. Klinz, F.J., Schmidt, A., Schinköthe, T., Arnhold, S., Desai, B., Popken, F., Brixius, K., Schwinger, R., Mehlhorn, U., Staib, P., Addicks, K., Bloch, W. Eur. J. Cell Biol. (2005) [Pubmed]
  32. Roles of 3-phosphoinositide-dependent kinase 1 in the regulation of endothelial nitric-oxide synthase phosphorylation and function by heat shock protein 90. Wei, Q., Xia, Y. J. Biol. Chem. (2005) [Pubmed]
  33. Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. Morrow, V.A., Foufelle, F., Connell, J.M., Petrie, J.R., Gould, G.W., Salt, I.P. J. Biol. Chem. (2003) [Pubmed]
  34. Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Santhanam, A.V., Smith, L.A., Akiyama, M., Rosales, A.G., Bailey, K.R., Katusic, Z.S. Stroke (2005) [Pubmed]
  35. Immunohistochemical localization of endothelial nitric oxide synthase in human testis, epididymis, and vas deferens suggests a possible role for nitric oxide in spermatogenesis, sperm maturation, and programmed cell death. Zini, A., O'Bryan, M.K., Magid, M.S., Schlegel, P.N. Biol. Reprod. (1996) [Pubmed]
  36. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) regulates endothelial nitric oxide synthase (eNOS) activity and its localization within the human vein endothelial cells (HUVEC) in culture. Di Pietro, R., Mariggiò, M.A., Guarnieri, S., Sancilio, S., Giardinelli, A., Di Silvestre, S., Consoli, A., Zauli, G., Pandolfi, A. J. Cell. Biochem. (2006) [Pubmed]
  37. NOSTRIN: a protein modulating nitric oxide release and subcellular distribution of endothelial nitric oxide synthase. Zimmermann, K., Opitz, N., Dedio, J., Renne, C., Muller-Esterl, W., Oess, S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  38. Altered endothelial nitric oxide synthase targeting and conformation and caveolin-1 expression in the diabetic kidney. Komers, R., Schutzer, W.E., Reed, J.F., Lindsley, J.N., Oyama, T.T., Buck, D.C., Mader, S.L., Anderson, S. Diabetes (2006) [Pubmed]
  39. Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Li, L., Haynes, M.P., Bender, J.R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  40. NOSIP, a novel modulator of endothelial nitric oxide synthase activity. Dedio, J., König, P., Wohlfart, P., Schroeder, C., Kummer, W., Müller-Esterl, W. FASEB J. (2001) [Pubmed]
  41. Nitric-oxide synthase (NOS) reductase domain models suggest a new control element in endothelial NOS that attenuates calmodulin-dependent activity. Knudsen, G.M., Nishida, C.R., Mooney, S.D., Ortiz de Montellano, P.R. J. Biol. Chem. (2003) [Pubmed]
  42. Endogenously generated nitric oxide by nitric-oxide synthase gene transfer inhibits cellular proliferation. Maeda, Y., Ikeda, U., Oya, K., Shimpo, M., Ueno, S., Okada, K., Saito, T., Mano, H., Ozawa, K., Shimada, K. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  43. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Kroll, J., Waltenberger, J. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  44. Distribution of nitric oxide synthase in normal and cirrhotic human liver. McNaughton, L., Puttagunta, L., Martinez-Cuesta, M.A., Kneteman, N., Mayers, I., Moqbel, R., Hamid, Q., Radomski, M.W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  45. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Lu, Q., Pallas, D.C., Surks, H.K., Baur, W.E., Mendelsohn, M.E., Karas, R.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  46. 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) [Pubmed]
  47. Taxotere-induced inhibition of human endothelial cell migration is a result of heat shock protein 90 degradation. Murtagh, J., Lu, H., Schwartz, E.L. Cancer Res. (2006) [Pubmed]
  48. Insulin-mediated venodilation is impaired in young, healthy carriers of the 825T allele of the G-protein beta3 subunit gene (GNB3). Mitchell, A., Pace, M., Nürnberger, J., Wenzel, R.R., Siffert, W., Philipp, T., Schäfers, R.F. Clin. Pharmacol. Ther. (2005) [Pubmed]
  49. Interrelated overexpression of endothelial and inducible nitric oxide synthases, endothelin-1 and angiogenic factors in human papillary thyroid carcinoma. Donckier, J.E., Michel, L., Delos, M., Havaux, X., Van Beneden, R. Clin. Endocrinol. (Oxf) (2006) [Pubmed]
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