Biology:Endothelial NOS

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Short description: Protein and coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7.[1] This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes.[2][3] The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain[4] and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases.[5] eNOS is primarily responsible for the generation of NO in the vascular endothelium,[6] a monolayer of flat cells lining the interior surface of blood vessels, at the interface between circulating blood in the lumen and the remainder of the vessel wall.[7] NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation.[8] Therefore, a functional eNOS is essential for a healthy cardiovascular system.

Structure and catalytic activities

eNOS is a dimer containing two identical monomers of 140 kD constituted by a reductase domain, which displays binding sites for nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD), and an oxidase domain, which displays binding sites for heme group, zinc, the cofactor tetrahydrobiopterin (BH4), and the substrate L-arginine.[9] The reductase domain is linked to the oxidase domain by a calmodulin-binding sequence.[10] In the vascular endothelium, NO is synthesized by eNOS from L-arginine and molecular oxygen, which binds to the heme group of eNOS, is reduced and finally incorporated into L- arginine to form NO and L-citrulline.[11][12] The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO.[13] In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled.[14] In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.[15][16]

Function

eNOS has a protective function in the cardiovascular system, which is attributed to NO production. Regulation of the vascular tone is one of the best known roles of NO in the cardiovascular system. Once produced in endothelial cells, NO diffuses across the vascular smooth muscle cell membranes and activates the enzyme soluble guanylate cyclase (sGC), which catalyzes the conversion of guanosine triphosphate into cyclic guanosine monophosphate (cGMP).[17] cGMP, in turn, activates protein kinase G (PKG), which promotes multiple phosphorylation of cellular targets lowering cellular Ca2+ concentrations and promoting vascular relaxation.[18] NO exerts antiproliferative effects by cGMP-dependent inhibiting Ca2+ influx or by directly inhibiting the activity of arginase and ornithine decarboxylase, decreasing the generation of polyamides required for DNA synthesis.[19][20] NO also has antithrombotic effects that result of its diffusion across platelet membrane and sGC activation, resulting in inhibition of platelet aggregation.[21] Moreover, NO affects leukocyte adhesion to the vascular endothelium by inhibiting the nuclear factor kappa B (NF-κB), which induces vascular endothelial expression of chemokines and adhesion molecules.[22] In addition to these functions, NO produced by eNOS has antioxidant properties as it reduces superoxide anion formation as a result of NO-induced increases in the expression of superoxide dismutase, an antioxidant enzyme that catalyzes the conversion of superoxide anion to hydrogen peroxide.[23] Furthermore, part of antioxidants properties of NO is attributable to up-regulation of heme-oxygenase-I and ferritin expression, which reduce superoxide anion concentrations in blood vessels.[24]

Regulation

eNOS expression and activity are carefully controlled by multiple interconnected mechanisms of regulation present at the transcriptional, posttranscriptional, and posttranslational levels. Binding of transcription factors such as Sp1, Sp3, Ets-1, Elf-1, and YY1 to the NOS3 promoter and DNA methylation represents an important mechanism of transcriptional regulation.[25] Posttranscriptionally, eNOS is regulated by modifications of the primary transcript, mRNA stability, subcellular localization, and nucleocytoplasmatic transport.[26] Posttranslational modifications of eNOS include fatty acid acylation, protein-protein interactions, substrate, and co-factor availability, and degree of phosphorylation. Importantly, eNOS is attached by myristoylation and palmitoylation to caveolae, a pocket-like invagination on the membrane rich in cholesterol and sphingolipids.[27] With the binding of eNOS to caveolae, the enzyme is inactivated due to the strong and direct interaction of eNOS with caveolin-1.[28] The binding of calcium-activated calmodulin to eNOS displaces caveolin-1 and activates eNOS. However, more recent studies have questioned the hypothesis that caveolin-1 directly binds to eNOS, as the region of the caveolin-1 protein proposed to bind to eNOS may be inaccessible due to its location in the plasma membrane. As a result, the specifics of how caveolin-1 interacts with eNOS to regulate eNOS activity are still unclear. [29] Moreover, eNOS activation is dynamically regulated by multiple phosphorylation sites at tyrosine, serine, and threonine residues.[9]

Clinical significance

Impaired NO production is involved in the pathogenesis of several diseases such as hypertension, preeclampsia, diabetes mellitus, obesity, erectile dysfunction, and migraine. In this regard, a large number of studies showed that polymorphisms in NOS3 gene affect the susceptibility to these diseases. Although NOS3 is a highly polymorphic gene, three genetic polymorphisms in this gene have been widely studied: the single nucleotide polymorphisms (SNPs) g.-786T>C (where "g." denotes genomic change which results in a Glu298Asp change in the coded protein), located in NOS3 promoter and in exon 7, respectively, and the variable number of tandem repeats (VNTR) characterized by 27 bp repeat in intron 4.[30] The C allele for the g.-786T>C polymorphism, which results in reduced eNOS expression and NO production,[31] was associated with increased risk for hypertension,[32] preeclampsia,[33] diabetic nephropathy,[34] and retinopathy,[35] migraine,[36] and erectile dysfunction.[37] The presence of ‘Asp’ allele for the Glu298Asp polymorphism reduces eNOS activity,[38] and was associated with higher susceptibility to hypertension,[39][40] preeclampsia,[41] diabetes mellitus,[42] migraine,[36] and erectile dysfunction.[43][44] The VNTR in intron 4 affects eNOS expression,[45] and the susceptibility to hypertension,[32] preeclampsia,[33] obesity,[46] and diabetes mellitus.[42] Growing evidence supports the association of diseases with NOS3 haplotypes (combination of alleles in close proximity, within a DNA block). This approach may be more informative than the analysis of genetic polymorphisms one by one.[47] Haplotypes including the SNPs g.-786T>C and Glu298Asp and the VNTR in intron 4 affected the susceptibility to hypertension,[48][49][50][51] preeclampsia,[52] and hypertension in diabetic subjects.[53] NOS3 variants may also affect the responses to drugs that affect NO signaling, such as statins, angiotensin-converting enzyme inhibitors (ACEi) and phosphodiesterase type 5 (PDE-5) inhibitors (PDE5i). Statin treatment was more effective in increasing NO bioavailability in subjects carrying the CC genotype for the g.-786T>C polymorphism than in TT carriers.[54][55] Hypertensive patients carrying the TC/CC genotypes and the C allele for the g.-786T>C polymorphism showed better antihypertensive responses to ACEi enalapril.[56] Likewise, patients with erectile dysfunction carrying the C allele for g.-786T>C polymorphism showed better responses to PDE-5 inhibitor sildenafil.[57][58] Together, these studies suggest that statins, ACEi and PDE-5 inhibitors may restore an impaired NO production in subjects carrying the variant allele/genotype for g.-786T>C NOS3 polymorphism, thus attenuating the cardiovascular risk. In addition to analysis of genetic polymorphisms individually, haplotypes including the SNPs g.-786T>C and Glu298Asp and the VNTR in intron 4 were shown to affect the responses to sildenafil in patients with erectile dysfunction.[57]

Notes

References

  1. ↑ "Molecular cloning and characterization of human endothelial nitric oxide synthase". FEBS Lett. 307 (3): 287–93. August 1992. doi:10.1016/0014-5793(92)80697-F. PMID 1379542. 
  2. ↑ "Exploring vascular benefits of endothelium-derived nitric oxide". American Journal of Hypertension 18 (12 Pt 2): 177S–183S. Dec 2005. doi:10.1016/j.amjhyper.2005.09.001. PMID 16373196. 
  3. ↑ "Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease". Free Radical Biology & Medicine 49 (3): 307–16. Aug 2010. doi:10.1016/j.freeradbiomed.2010.04.004. PMID 20388537. 
  4. ↑ "Nitric oxide synthases: regulation and function". European Heart Journal 33 (7): 829–37, 837a–837d. Apr 2012. doi:10.1093/eurheartj/ehr304. PMID 21890489. 
  5. ↑ "Inducible nitric oxide synthase as a possible target in hypertension". Current Drug Targets 15 (2): 164–74. Feb 2014. doi:10.2174/13894501113146660227. PMID 24102471. 
  6. ↑ "Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium". Cellular and Molecular Life Sciences 63 (2): 144–62. Jan 2006. doi:10.1007/s00018-005-5421-8. PMID 16416260. 
  7. ↑ "Cells in focus: endothelial cell". The International Journal of Biochemistry & Cell Biology 34 (12): 1508–12. Dec 2002. doi:10.1016/s1357-2725(02)00075-4. PMID 12379270. 
  8. ↑ "Endothelial nitric oxide synthase in vascular disease: from marvel to menace". Circulation 113 (13): 1708–14. Apr 2006. doi:10.1161/CIRCULATIONAHA.105.602532. PMID 16585403. 
  9. ↑ 9.0 9.1 "Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium". Frontiers in Physiology 4: 347. 2013. doi:10.3389/fphys.2013.00347. PMID 24379783. 
  10. ↑ "Nitric oxide synthases: structure, function and inhibition". The Biochemical Journal 357 (Pt 3): 593–615. Aug 2001. doi:10.1042/bj3570593. PMID 11463332. 
  11. ↑ "Signal transduction of eNOS activation". Cardiovascular Research 43 (3): 532–41. Aug 1999. doi:10.1016/s0008-6363(99)00094-2. PMID 10690325. 
  12. ↑ "Free radical production by dysfunctional eNOS". Heart 90 (5): 494–5. May 2004. doi:10.1136/hrt.2003.029405. PMID 15084540. 
  13. ↑ "The regulation and pharmacology of endothelial nitric oxide synthase". Annual Review of Pharmacology and Toxicology 46: 235–76. 2006. doi:10.1146/annurev.pharmtox.44.101802.121844. PMID 16402905. 
  14. ↑ "Subcellular localization of oxidants and redox modulation of endothelial nitric oxide synthase". Circulation Journal 76 (11): 2497–512. 2012. doi:10.1253/circj.cj-12-1207. PMID 23075817. 
  15. ↑ "Protective role of endothelial nitric oxide synthase". The Journal of Pathology 199 (1): 8–17. Jan 2003. doi:10.1002/path.1250. PMID 12474221. 
  16. ↑ "Molecular mechanisms of endothelial NO synthase uncoupling". Current Pharmaceutical Design 20 (22): 3548–53. 2014. doi:10.2174/13816128113196660746. PMID 24180388. 
  17. ↑ "Guanylate cyclase and the .NO/cGMP signaling pathway". Biochimica et Biophysica Acta 1411 (2–3): 334–50. May 1999. doi:10.1016/s0005-2728(99)00024-9. PMID 10320667. 
  18. ↑ "Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha". Science 286 (5444): 1583–7. Nov 1999. doi:10.1126/science.286.5444.1583. PMID 10567269. 
  19. ↑ "Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP". The American Journal of Physiology 267 (5 Pt 1): C1405–13. Nov 1994. doi:10.1152/ajpcell.1994.267.5.C1405. PMID 7977701. 
  20. ↑ "Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation". Proceedings of the National Academy of Sciences of the United States of America 98 (7): 4202–8. Mar 2001. doi:10.1073/pnas.071054698. PMID 11259671. 
  21. ↑ "Nitric oxide in vascular biology". Journal of Thrombosis and Haemostasis 1 (10): 2112–8. Oct 2003. doi:10.1046/j.1538-7836.2003.00345.x. PMID 14521592. 
  22. ↑ "New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases". Clinical Chemistry 45 (1): 7–17. Jan 1999. doi:10.1093/clinchem/45.1.7. PMID 9895331. 
  23. ↑ "Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training". The Journal of Clinical Investigation 105 (11): 1631–9. Jun 2000. doi:10.1172/JCI9551. PMID 10841522. 
  24. ↑ "Ferritin: a cytoprotective antioxidant strategem of endothelium". The Journal of Biological Chemistry 267 (25): 18148–53. Sep 1992. doi:10.1016/S0021-9258(19)37165-0. PMID 1517245. 
  25. ↑ "Characterization of the human endothelial nitric-oxide synthase promoter". The Journal of Biological Chemistry 274 (5): 3076–93. Jan 1999. doi:10.1074/jbc.274.5.3076. PMID 9915847. 
  26. ↑ "Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression". American Journal of Physiology. Cell Physiology 291 (5): C803–16. Nov 2006. doi:10.1152/ajpcell.00457.2005. PMID 16738003. 
  27. ↑ "Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis". Trends in Cell Biology 4 (7): 231–5. Jul 1994. doi:10.1016/0962-8924(94)90114-7. PMID 14731661. 
  28. ↑ "Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity". The Journal of Biological Chemistry 272 (30): 18522–5. Jul 1997. doi:10.1074/jbc.272.30.18522. PMID 9228013. 
  29. ↑ "Structure-based Reassessment of the Caveolin Signaling Model: Do Caveolae Regulate Signaling Through Caveolin-Protein Interactions?". Dev Cell 23 (1): 11–20. Jun 2012. doi:10.1016/j.devcel.2012.06.012. PMID 3427029. 
  30. ↑ "A pharmacogenetics-based approach to reduce cardiovascular mortality with the prophylactic use of statins". Basic & Clinical Pharmacology & Toxicology 106 (5): 357–61. May 2010. doi:10.1111/j.1742-7843.2010.00551.x. PMID 20210789. 
  31. ↑ "T-786→C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm". Circulation 99 (22): 2864–70. Jun 1999. doi:10.1161/01.cir.99.22.2864. PMID 10359729. 
  32. ↑ 32.0 32.1 "An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension". PLOS ONE 6 (9): e24266. 2011. doi:10.1371/journal.pone.0024266. PMID 21912683. Bibcode: 2011PLoSO...624266N. 
  33. ↑ 33.0 33.1 "The polymorphism for endothelial nitric oxide synthase gene, the level of nitric oxide and the risk for pre-eclampsia: a meta-analysis". Gene 519 (1): 187–93. Apr 2013. doi:10.1016/j.gene.2013.01.004. PMID 23375994. 
  34. ↑ "Endothelial nitric oxide synthase gene polymorphisms and the risk of diabetic nephropathy in type 2 diabetes mellitus". Genetic Testing and Molecular Biomarkers 16 (6): 574–9. Jun 2012. doi:10.1089/gtmb.2011.0218. PMID 22313046. 
  35. ↑ "The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy". Nitric Oxide 13 (1): 88–92. Aug 2005. doi:10.1016/j.niox.2005.04.004. PMID 15890549. 
  36. ↑ 36.0 36.1 "Association of endothelial nitric oxide synthase gene polymorphisms (894G/T, -786T/C, G10T) and clinical findings in patients with migraine". Neuromolecular Medicine 16 (3): 587–93. Sep 2014. doi:10.1007/s12017-014-8311-0. PMID 24845269. 
  37. ↑ "Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects". BJU International 107 (12): 1994–2001. Jun 2011. doi:10.1111/j.1464-410X.2010.09755.x. PMID 20955262. 
  38. ↑ "Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear". FASEB Journal 21 (11): 2655–63. Sep 2007. doi:10.1096/fj.06-7088com. PMID 17449720. 
  39. ↑ "The association between endothelial nitric oxide synthase gene G894T polymorphism and hypertension in Han Chinese: a case-control study and an updated meta-analysis". Annals of Human Biology 42 (2): 184–94. Mar 2015. doi:10.3109/03014460.2014.911958. PMID 24846690. 
  40. ↑ "Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias". Journal of Hypertension 25 (9): 1763–74. Sep 2007. doi:10.1097/HJH.0b013e3281de740d. PMID 17762636. 
  41. ↑ "Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study". Hypertension 44 (5): 702–7. Nov 2004. doi:10.1161/01.HYP.0000143483.66701.ec. PMID 15364897. 
  42. ↑ 42.0 42.1 "Association of endothelial nitric oxide synthase gene polymorphisms with type 2 diabetes mellitus: a meta-analysis". Endocrine Journal 60 (7): 893–901. 2013. doi:10.1507/endocrj.ej12-0463. PMID 23563728. 
  43. ↑ "The association of eNOS G894T polymorphism with metabolic syndrome and erectile dysfunction". The Journal of Sexual Medicine 9 (3): 837–43. Mar 2012. doi:10.1111/j.1743-6109.2011.02588.x. PMID 22304542. 
  44. ↑ "eNOS [Glu298Asp] polymorphism, erectile function and ocular pressure in type 2 diabetes". European Journal of Clinical Investigation 42 (7): 729–37. Jul 2012. doi:10.1111/j.1365-2362.2011.02638.x. PMID 22224829. 
  45. ↑ "Effect of 27nt small RNA on endothelial nitric-oxide synthase expression". Molecular Biology of the Cell 19 (9): 3997–4005. Sep 2008. doi:10.1091/mbc.E07-11-1186. PMID 18614799. 
  46. ↑ "eNOS haplotype associated with hypertension in obese children and adolescents". International Journal of Obesity 35 (3): 387–92. Mar 2011. doi:10.1038/ijo.2010.146. PMID 20661250. 
  47. ↑ "Definition and clinical importance of haplotypes". Annual Review of Medicine 56: 303–20. 2005. doi:10.1146/annurev.med.56.082103.104540. PMID 15660514. 
  48. ↑ "Susceptible and protective eNOS haplotypes in hypertensive black and white subjects". Atherosclerosis 186 (2): 428–32. Jun 2006. doi:10.1016/j.atherosclerosis.2005.08.003. PMID 16168996. 
  49. ↑ "Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus". Atherosclerosis 189 (1): 241–6. Nov 2006. doi:10.1016/j.atherosclerosis.2005.12.011. PMID 16427644. 
  50. ↑ "Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy". Journal of Hypertension 24 (12): 2393–7. Dec 2006. doi:10.1097/01.hjh.0000251899.47626.4f. PMID 17082721. 
  51. ↑ "Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy". DNA and Cell Biology 29 (4): 171–6. Apr 2010. doi:10.1089/dna.2009.0955. PMID 20070154. 
  52. ↑ "Effects of eNOS polymorphisms on nitric oxide formation in healthy pregnancy and in pre-eclampsia". Molecular Human Reproduction 16 (7): 506–10. Jul 2010. doi:10.1093/molehr/gaq030. PMID 20457799. 
  53. ↑ "Endothelial nitric oxide synthase genotype and haplotype are not associated with diabetic retinopathy in diabetes type 2 patients". Nitric Oxide 15 (4): 417–22. Dec 2006. doi:10.1016/j.niox.2006.02.002. PMID 16581274. 
  54. ↑ "eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite". Free Radical Biology & Medicine 41 (7): 1044–9. Oct 2006. doi:10.1016/j.freeradbiomed.2006.04.026. PMID 16962929. 
  55. ↑ "Simvastatin treatment increases nitrite levels in obese women: modulation by T(-786)C polymorphism of eNOS". Nitric Oxide 33: 83–7. Sep 2013. doi:10.1016/j.niox.2013.07.005. PMID 23876348. 
  56. ↑ "eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril". European Journal of Clinical Pharmacology 69 (2): 167–77. Feb 2013. doi:10.1007/s00228-012-1326-2. PMID 22706620. 
  57. ↑ 57.0 57.1 "Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction". The Pharmacogenomics Journal 13 (2): 189–96. Apr 2013. doi:10.1038/tpj.2011.49. PMID 22064666. 
  58. ↑ "Pharmacogenetics of erectile dysfunction: navigating into uncharted waters". Pharmacogenomics 15 (11): 1519–38. Aug 2014. doi:10.2217/pgs.14.110. PMID 25303302. 

Further reading



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