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Gene Review

NOS3  -  nitric oxide synthase 3 (endothelial cell)

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Disease relevance of NOS3


Psychiatry related information on NOS3

  • The time response studies show that HPODE treatment significantly increased eNOS mRNA levels at 12 and 24 h [6].

High impact information on NOS3


Chemical compound and disease context of NOS3


Biological context of NOS3


Anatomical context of NOS3


Associations of NOS3 with chemical compounds

  • Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow [1].
  • The proline-rich domain of dynamin-2 is responsible for dynamin-dependent in vitro potentiation of endothelial nitric-oxide synthase activity via selective effects on reductase domain function [17].
  • In this study, we found that either FSS or insulin stimulated insulin receptor substrate-1 (IRS-1) tyrosine and serine phosphorylation and increased IRS-1-associated phosphatidylinositol 3-kinase activity, phosphorylation of PKB Ser-473, phosphorylation of eNOS Ser-1179, and NO production [18].
  • The nocodazole-induced redistribution of eNOS is similar to that of cis-, medial-, and trans-Golgi markers, while the caveolin-1 redistribution resembles that of sec22, a marker for the intermediate compartment [16].
  • Alanine scanning of AP-Cav-B revealed that Thr-90 and -91 (T90,91) and Phe-92 (F92) are crucial for AP-Cav-B- and AP-Cav-mediated inhibition of eNOS [19].

Physical interactions of NOS3

  • Recent evidence has shown that eNOS can co-precipitate with caveolin-1, the resident coat protein of caveolae, suggesting a direct interaction between these two proteins [20].
  • VEGF had no effect on the binding of Hsp90 with eNOS, whereas 20-HETE decreased the association of the protein partners [21].
  • Furthermore, an inhibitor of NF-kappaB translocation, pyrrolidine dithiocarbamate failed to modify both the downregulation of eNOS expression and the increased binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA by TNF-alpha [22].

Enzymatic interactions of NOS3

  • Finally, PKB phosphorylated eNOS in vitro at the same site phosphorylated in the cell and increased eNOS enzymatic activity by 15-20-fold [23].

Co-localisations of NOS3


Regulatory relationships of NOS3


Other interactions of NOS3

  • Collectively, our results show that the actions of CaM on eNOS dissociation from caveolin are facilitated in the presence of hsp90 [27].
  • Here we demonstrate, using purified proteins, that this occurs through a selective influence of the dyn-2 proline-rich domain (dyn-2 PRD) on the eNOS reductase domain [17].
  • We have demonstrated that VEGF-induced dilation of bovine pulmonary arteries is associated with activation of cytochrome P-450 family 4 (CYP4) enzymes and eNOS [21].
  • Sphingosine 1-phosphate (S1P) is a platelet-derived sphingolipid that binds to S1P1 (EDG-1) receptors and activates the endothelial isoform of NO synthase (eNOS) [28].
  • Densitometry showed that Flk-1/KDR, eNOS, and caveolin-1 levels were highest in caveolar fractions [24].

Analytical, diagnostic and therapeutic context of NOS3


  1. Cyclosporin A inhibits flow-mediated activation of endothelial nitric-oxide synthase by altering cholesterol content in caveolae. Lungu, A.O., Jin, Z.G., Yamawaki, H., Tanimoto, T., Wong, C., Berk, B.C. J. Biol. Chem. (2004) [Pubmed]
  2. Tumor necrosis factor-alpha inhibits endothelial nitric-oxide synthase gene promoter activity in bovine aortic endothelial cells. Anderson, H.D., Rahmutula, D., Gardner, D.G. J. Biol. Chem. (2004) [Pubmed]
  3. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. Du, X.L., Edelstein, D., Dimmeler, S., Ju, Q., Sui, C., Brownlee, M. J. Clin. Invest. (2001) [Pubmed]
  4. Endothelial cytosolic proteins bind to the 3' untranslated region of endothelial nitric oxide synthase mRNA: regulation by tumor necrosis factor alpha. Alonso, J., Sánchez de Miguel, L., Montón, M., Casado, S., López-Farré, A. Mol. Cell. Biol. (1997) [Pubmed]
  5. Overexpression of endothelial nitric oxide synthase in transgenic mice accelerates testicular germ cell apoptosis induced by experimental cryptorchidism. Ishikawa, T., Kondo, Y., Goda, K., Fujisawa, M. J. Androl. (2005) [Pubmed]
  6. Regulation of endothelial nitric oxide synthase gene expression by oxidized linoleic acid. Ramasamy, S., Parthasarathy, S., Harrison, D.G. J. Lipid Res. (1998) [Pubmed]
  7. Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Raman, C.S., Li, H., Martásek, P., Král, V., Masters, B.S., Poulos, T.L. Cell (1998) [Pubmed]
  8. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. Zou, M.H., Shi, C., Cohen, R.A. J. Clin. Invest. (2002) [Pubmed]
  9. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. Limbourg, F.P., Huang, Z., Plumier, J.C., Simoncini, T., Fujioka, M., Tuckermann, J., Schütz, G., Moskowitz, M.A., Liao, J.K. J. Clin. Invest. (2002) [Pubmed]
  10. Diabetic mouse angiopathy is linked to progressive sympathetic receptor deletion coupled to an enhanced caveolin-1 expression. Bucci, M., Roviezzo, F., Brancaleone, V., Lin, M.I., Di Lorenzo, A., Cicala, C., Pinto, A., Sessa, W.C., Farneti, S., Fiorucci, S., Cirino, G. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]
  11. Opposing effects of reactive oxygen species and cholesterol on endothelial nitric oxide synthase and endothelial cell caveolae. Peterson, T.E., Poppa, V., Ueba, H., Wu, A., Yan, C., Berk, B.C. Circ. Res. (1999) [Pubmed]
  12. Endothelial nitric-oxide synthase. Expression in Escherichia coli, spectroscopic characterization, and role of tetrahydrobiopterin in dimer formation. Rodríguez-Crespo, I., Gerber, N.C., Ortiz de Montellano, P.R. J. Biol. Chem. (1996) [Pubmed]
  13. Regulation of endothelial nitric oxide synthase by protein kinase C. Matsubara, M., Hayashi, N., Jing, T., Titani, K. J. Biochem. (2003) [Pubmed]
  14. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. Michel, J.B., Feron, O., Sacks, D., Michel, T. J. Biol. Chem. (1997) [Pubmed]
  15. Direct interaction between endothelial nitric-oxide synthase and dynamin-2. Implications for nitric-oxide synthase function. Cao, S., Yao, J., McCabe, T.J., Yao, Q., Katusic, Z.S., Sessa, W.C., Shah, V. J. Biol. Chem. (2001) [Pubmed]
  16. Endothelial nitric oxide synthase and its negative regulator caveolin-1 localize to distinct perinuclear organelles. Govers, R., van der Sluijs, P., van Donselaar, E., Slot, J.W., Rabelink, T.J. J. Histochem. Cytochem. (2002) [Pubmed]
  17. The proline-rich domain of dynamin-2 is responsible for dynamin-dependent in vitro potentiation of endothelial nitric-oxide synthase activity via selective effects on reductase domain function. Cao, S., Yao, J., Shah, V. J. Biol. Chem. (2003) [Pubmed]
  18. TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells. Kim, F., Gallis, B., Corson, M.A. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  19. Dissecting the molecular control of endothelial NO synthase by caveolin-1 using cell-permeable peptides. Bernatchez, P.N., Bauer, P.M., Yu, J., Prendergast, J.S., He, P., Sessa, W.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  20. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. García-Cardeña, G., Martasek, P., Masters, B.S., Skidd, P.M., Couet, J., Li, S., Lisanti, M.P., Sessa, W.C. J. Biol. Chem. (1997) [Pubmed]
  21. Mechanisms of activation of eNOS by 20-HETE and VEGF in bovine pulmonary artery endothelial cells. Chen, Y., Medhora, M., Falck, J.R., Pritchard, K.A., Jacobs, E.R. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  22. Cerivastatin prevents tumor necrosis factor-alpha-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins. González-Fernández, F., Jiménez, A., López-Blaya, A., Velasco, S., Arriero, M.M., Celdrán, A., Rico, L., Farré, J., Casado, S., López-Farré, A. Atherosclerosis (2001) [Pubmed]
  23. Identification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002. Gallis, B., Corthals, G.L., Goodlett, D.R., Ueba, H., Kim, F., Presnell, S.R., Figeys, D., Harrison, D.G., Berk, B.C., Aebersold, R., Corson, M.A. J. Biol. Chem. (1999) [Pubmed]
  24. VEGF-induced permeability increase is mediated by caveolae. Feng, Y., Venema, V.J., Venema, R.C., Tsai, N., Behzadian, M.A., Caldwell, R.B. Invest. Ophthalmol. Vis. Sci. (1999) [Pubmed]
  25. Hepatocyte growth factor activates endothelial nitric oxide synthase by Ca(2+)- and phosphoinositide 3-kinase/Akt-dependent phosphorylation in aortic endothelial cells. Makondo, K., Kimura, K., Kitamura, N., Kitamura, T., Yamaji, D., Jung, B.D., Saito, M. Biochem. J. (2003) [Pubmed]
  26. Akt-dependent phosphorylation of serine 1179 and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 cooperatively mediate activation of the endothelial nitric-oxide synthase by hydrogen peroxide. Cai, H., Li, Z., Davis, M.E., Kanner, W., Harrison, D.G., Dudley, S.C. Mol. Pharmacol. (2003) [Pubmed]
  27. Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1. Gratton, J.P., Fontana, J., O'Connor, D.S., Garcia-Cardena, G., McCabe, T.J., Sessa, W.C. J. Biol. Chem. (2000) [Pubmed]
  28. VEGF induces S1P1 receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors. Igarashi, J., Erwin, P.A., Dantas, A.P., Chen, H., Michel, T. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  29. Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Lamas, S., Marsden, P.A., Li, G.K., Tempst, P., Michel, T. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  30. Role of the interdomain linker probed by kinetics of CO ligation to an endothelial nitric oxide synthase mutant lacking the calmodulin binding peptide (residues 503-517 in bovine). Zemojtel, T., Scheele, J.S., Martásek, P., Masters, B.S., Sharma, V.S., Magde, D. Biochemistry (2003) [Pubmed]
  31. Receptor-regulated dynamic interaction between endothelial nitric oxide synthase and calmodulin revealed by fluorescence resonance energy transfer in living cells. Jobin, C.M., Chen, H., Lin, A.J., Yacono, P.W., Igarashi, J., Michel, T., Golan, D.E. Biochemistry (2003) [Pubmed]
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