Просмотр кода страницы Английская Википедия:Endothelial NOS

{{Английская Википедия/Панель перехода}}
{{Short description|Protein and coding gene in humans}}
{{Infobox_gene}}
'''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.<ref name="pmid1379542">{{cite journal |vauthors=Marsden PA, Schappert KT, Chen HS, Flowers M, Sundell CL, Wilcox JN, Lamas S, Michel T | title = Molecular cloning and characterization of human endothelial nitric oxide synthase | journal = FEBS Lett. | volume = 307 | issue = 3 | pages = 287–93 |date=August 1992 | pmid = 1379542 | doi = 10.1016/0014-5793(92)80697-F| s2cid = 36429463 | doi-access = free }}</ref>  This enzyme is one of three [[protein isoform|isoforms]] that synthesize [[nitric oxide]] (NO), a small gaseous and lipophilic molecule that participates in several biological processes.<ref>{{cite journal | vauthors = Cockcroft JR | title = Exploring vascular benefits of endothelium-derived nitric oxide | journal = American Journal of Hypertension | volume = 18 | issue = 12 Pt 2 | pages = 177S–183S | date = Dec 2005 | pmid = 16373196 | doi = 10.1016/j.amjhyper.2005.09.001 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Villanueva C, Giulivi C | title = Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease | journal = Free Radical Biology & Medicine | volume = 49 | issue = 3 | pages = 307–16 | date = Aug 2010 | pmid = 20388537 | doi = 10.1016/j.freeradbiomed.2010.04.004 | pmc=2900489}}</ref> The other isoforms include [[neuronal nitric oxide synthase]] (nNOS), which is constitutively expressed in specific neurons of the brain<ref>{{cite journal | vauthors = Förstermann U, Sessa WC | title = Nitric oxide synthases: regulation and function | journal = European Heart Journal | volume = 33 | issue = 7 | pages = 829–37, 837a–837d | date = Apr 2012 | pmid = 21890489 | doi = 10.1093/eurheartj/ehr304 | pmc=3345541}}</ref> and [[inducible nitric oxide synthase]] (iNOS), whose expression is typically induced in [[inflammatory disease]]s.<ref>{{cite journal | vauthors = Oliveira-Paula GH, Lacchini R, Tanus-Santos JE | title = Inducible nitric oxide synthase as a possible target in hypertension | journal = Current Drug Targets | volume = 15 | issue = 2 | pages = 164–74 | date = Feb 2014 | pmid = 24102471 | doi=10.2174/13894501113146660227}}</ref> 
eNOS is primarily responsible for the generation of NO in the [[endothelium|vascular endothelium]],<ref>{{cite journal | vauthors = Fish JE, Marsden PA | title = Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium | journal = Cellular and Molecular Life Sciences | volume = 63 | issue = 2 | pages = 144–62 | date = Jan 2006 | pmid = 16416260 | doi = 10.1007/s00018-005-5421-8 | s2cid = 22111996 }}</ref> 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.<ref>{{cite journal | vauthors = Sumpio BE, Riley JT, Dardik A | title = Cells in focus: endothelial cell | journal = The International Journal of Biochemistry & Cell Biology | volume = 34 | issue = 12 | pages = 1508–12 | date = Dec 2002 | pmid = 12379270 | doi=10.1016/s1357-2725(02)00075-4}}</ref> NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, [[leukocyte]] adhesion, and [[platelet aggregation]].<ref>{{cite journal | vauthors = Förstermann U, Münzel T | title = Endothelial nitric oxide synthase in vascular disease: from marvel to menace | journal = Circulation | volume = 113 | issue = 13 | pages = 1708–14 | date = Apr 2006 | pmid = 16585403 | doi = 10.1161/CIRCULATIONAHA.105.602532 | doi-access = free }}</ref> 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]].<ref name="Qian J 2013">{{cite journal | vauthors = Qian J, Fulton D | title = Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium | journal = Frontiers in Physiology | volume = 4 | pages = 347 | pmid = 24379783 | doi = 10.3389/fphys.2013.00347 | year=2013 | pmc=3861784| doi-access = free }}</ref> The reductase domain is linked to the oxidase domain by a [[calmodulin]]-binding sequence.<ref>{{cite journal | vauthors = Alderton WK, Cooper CE, Knowles RG | title = Nitric oxide synthases: structure, function and inhibition | journal = The Biochemical Journal | volume = 357 | issue = Pt 3 | pages = 593–615 | date = Aug 2001 | pmid = 11463332 | doi=10.1042/bj3570593 | pmc=1221991}}</ref>
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]].<ref>{{cite journal | vauthors = Fleming I, Busse R | title = Signal transduction of eNOS activation | journal = Cardiovascular Research | volume = 43 | issue = 3 | pages = 532–41 | date = Aug 1999 | pmid = 10690325 | doi=10.1016/s0008-6363(99)00094-2| doi-access = free }}</ref><ref>{{cite journal | vauthors = Verhaar MC, Westerweel PE, van Zonneveld AJ, Rabelink TJ | title = Free radical production by dysfunctional eNOS | journal = Heart | volume = 90 | issue = 5 | pages = 494–5 | date = May 2004 | pmid = 15084540 | doi=10.1136/hrt.2003.029405 | pmc=1768213}}</ref> The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO.<ref>{{cite journal | vauthors = Dudzinski DM, Igarashi J, Greif D, Michel T | title = The regulation and pharmacology of endothelial nitric oxide synthase | journal = Annual Review of Pharmacology and Toxicology | volume = 46 | pages = 235–76 | pmid = 16402905 | doi = 10.1146/annurev.pharmtox.44.101802.121844 | year=2006}}</ref> In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled.<ref>{{cite journal | vauthors = Maron BA, Michel T | title = Subcellular localization of oxidants and redox modulation of endothelial nitric oxide synthase | journal = Circulation Journal | volume = 76 | issue = 11 | pages = 2497–512 | pmid = 23075817 | doi=10.1253/circj.cj-12-1207 | year=2012| doi-access = free }}</ref> In this conformation, instead of synthesizing NO, eNOS produces [[superoxide anion]], a highly reactive [[free radical]] with deleterious consequences to the cardiovascular system.<ref>{{cite journal | vauthors = Albrecht EW, Stegeman CA, Heeringa P, Henning RH, van Goor H | title = Protective role of endothelial nitric oxide synthase | journal = The Journal of Pathology | volume = 199 | issue = 1 | pages = 8–17 | date = Jan 2003 | pmid = 12474221 | doi = 10.1002/path.1250 | s2cid = 24066479 }}</ref><ref>{{cite journal | vauthors = Luo S, Lei H, Qin H, Xia Y | title = Molecular mechanisms of endothelial NO synthase uncoupling | journal = Current Pharmaceutical Design | volume = 20 | issue = 22 | pages = 3548–53 | pmid = 24180388 | doi=10.2174/13816128113196660746 | year=2014}}</ref>

== 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).<ref>{{cite journal | vauthors = Denninger JW, Marletta MA | title = Guanylate cyclase and the .NO/cGMP signaling pathway | journal = Biochimica et Biophysica Acta | volume = 1411 | issue = 2–3 | pages = 334–50 | date = May 1999 | pmid = 10320667 | doi=10.1016/s0005-2728(99)00024-9| doi-access = free }}</ref> cGMP, in turn, activates protein kinase G (PKG), which promotes multiple phosphorylation of cellular targets lowering cellular [[Calcium in biology|Ca<sup>2+</sup>]] concentrations and promoting vascular relaxation.<ref>{{cite journal | vauthors = Surks HK, Mochizuki N, Kasai Y, Georgescu SP, Tang KM, Ito M, Lincoln TM, Mendelsohn ME | title = Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha | journal = Science | volume = 286 | issue = 5444 | pages = 1583–7 | date = Nov 1999 | pmid = 10567269 | doi=10.1126/science.286.5444.1583}}</ref>
NO exerts antiproliferative effects by cGMP-dependent inhibiting Ca<sup>2+</sup> influx or by directly inhibiting the activity of arginase and ornithine decarboxylase, decreasing the generation of polyamides required for DNA synthesis.<ref>{{cite journal | vauthors = Cornwell TL, Arnold E, Boerth NJ, Lincoln TM | title = Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP | journal = The American Journal of Physiology | volume = 267 | issue = 5 Pt 1 | pages = C1405–13 | date = Nov 1994 | pmid = 7977701 | doi = 10.1152/ajpcell.1994.267.5.C1405 }}</ref><ref>{{cite journal | vauthors = Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, del Soldato P | title = Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 7 | pages = 4202–8 | date = Mar 2001 | pmid = 11259671 | doi = 10.1073/pnas.071054698 | pmc=31203| doi-access = free }}</ref> NO also has antithrombotic effects that result of its diffusion across platelet membrane and sGC activation, resulting in inhibition of platelet aggregation.<ref>{{cite journal | vauthors = Walford G, Loscalzo J | title = Nitric oxide in vascular biology | journal = Journal of Thrombosis and Haemostasis | volume = 1 | issue = 10 | pages = 2112–8 | date = Oct 2003 | pmid = 14521592 | doi=10.1046/j.1538-7836.2003.00345.x| s2cid = 22128603 | doi-access = free }}</ref> Moreover, NO affects leukocyte adhesion to the vascular endothelium by inhibiting the  nuclear factor kappa B ([[NF-κB]]), which induces vascular endothelial expression of [[chemokine]]s and adhesion molecules.<ref>{{cite journal | vauthors = Chen F, Castranova V, Shi X, Demers LM | title = New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases | journal = Clinical Chemistry | volume = 45 | issue = 1 | pages = 7–17 | date = Jan 1999 | doi = 10.1093/clinchem/45.1.7 | pmid = 9895331 | doi-access = free }}</ref>
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]].<ref>{{cite journal | vauthors = Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y, Kojda G, Harrison DG | title = Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training | journal = The Journal of Clinical Investigation | volume = 105 | issue = 11 | pages = 1631–9 | date = Jun 2000 | pmid = 10841522 | doi = 10.1172/JCI9551 | pmc=300857}}</ref> 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.<ref>{{cite journal | vauthors = Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM | title = Ferritin: a cytoprotective antioxidant strategem of endothelium | journal = The Journal of Biological Chemistry | volume = 267 | issue = 25 | pages = 18148–53 | date = Sep 1992 | doi = 10.1016/S0021-9258(19)37165-0 | pmid = 1517245 | doi-access = free | hdl = 2437/120319 | hdl-access = free }}</ref>

== 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 transcription factor|Sp1]], [[Sp3 transcription factor|Sp3]], [[Ets-1]], [[ELF1|Elf-1]], and [[YY1]] to the NOS3 [[gene promoter|promoter]] and [[DNA methylation]] represents an important mechanism of transcriptional regulation.<ref>{{cite journal | vauthors = Karantzoulis-Fegaras F, Antoniou H, Lai SL, Kulkarni G, D'Abreo C, Wong GK, Miller TL, Chan Y, Atkins J, Wang Y, Marsden PA | title = Characterization of the human endothelial nitric-oxide synthase promoter | journal = The Journal of Biological Chemistry | volume = 274 | issue = 5 | pages = 3076–93 | date = Jan 1999 | pmid = 9915847 | doi=10.1074/jbc.274.5.3076| doi-access = free }}</ref> Posttranscriptionally, eNOS is regulated by modifications of the primary transcript, mRNA stability, subcellular localization, and nucleocytoplasmatic transport.<ref>{{cite journal | vauthors = Searles CD | title = Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression | journal = American Journal of Physiology. Cell Physiology | volume = 291 | issue = 5 | pages = C803–16 | date = Nov 2006 | pmid = 16738003 | doi = 10.1152/ajpcell.00457.2005 }}</ref> 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 [[sphingolipid]]s.<ref>{{cite journal | vauthors = Lisanti MP, Scherer PE, Tang Z, Sargiacomo M | title = Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis | journal = Trends in Cell Biology | volume = 4 | issue = 7 | pages = 231–5 | date = Jul 1994 | pmid = 14731661 | doi=10.1016/0962-8924(94)90114-7}}</ref> With the binding of eNOS to caveolae, the enzyme is inactivated due to the strong and direct interaction of eNOS with [[caveolin 1|caveolin-1]].<ref>{{cite journal | vauthors = Ju H, Zou R, Venema VJ, Venema RC | title = Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18522–5 | date = Jul 1997 | pmid = 9228013 | doi=10.1074/jbc.272.30.18522| doi-access = free }}</ref> 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. <ref>{{cite journal | vauthors = Collins B, Davis M, Hancock J, Parton R | title = Structure-based Reassessment of the Caveolin Signaling Model: Do Caveolae Regulate Signaling Through Caveolin-Protein Interactions? | journal = Dev Cell | volume = 23 | issue = 1 | pages = 11–20 | date = Jun 2012 | pmid = 3427029 | doi = 10.1016/j.devcel.2012.06.012|pmc=3427029}}</ref> Moreover, eNOS activation is dynamically regulated by multiple phosphorylation sites at [[tyrosine]], [[serine]], and [[threonine]] residues.<ref name="Qian J 2013"/>

== 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 [[polymorphism (biology)|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.<ref>{{cite journal | vauthors = Lacchini R, Silva PS, Tanus-Santos JE | title = A pharmacogenetics-based approach to reduce cardiovascular mortality with the prophylactic use of statins | journal = Basic & Clinical Pharmacology & Toxicology | volume = 106 | issue = 5 | pages = 357–61 | date = May 2010 | pmid = 20210789 | doi = 10.1111/j.1742-7843.2010.00551.x | doi-access = free }}</ref> The C allele for the g.-786T>C polymorphism, which results in reduced eNOS expression and NO production,<ref>{{cite journal | vauthors = Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, Motoyama T, Saito Y, Ogawa Y, Miyamoto Y, Nakao K | title = T-786→C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm | journal = Circulation | volume = 99 | issue = 22 | pages = 2864–70 | date = Jun 1999 | pmid = 10359729 | doi=10.1161/01.cir.99.22.2864| doi-access = free }}</ref> was associated with increased risk for hypertension,<ref name="ReferenceA">{{cite journal | vauthors = Niu W, Qi Y | title = An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension | journal = PLOS ONE | volume = 6 | issue = 9 | pages = e24266 | pmid = 21912683 | doi = 10.1371/journal.pone.0024266 | year=2011 | pmc=3166328| bibcode = 2011PLoSO...624266N | doi-access = free }}</ref> preeclampsia,<ref name="Dai B 2013">{{cite journal | vauthors = Dai B, Liu T, Zhang B, Zhang X, Wang Z | title = The polymorphism for endothelial nitric oxide synthase gene, the level of nitric oxide and the risk for pre-eclampsia: a meta-analysis | journal = Gene | volume = 519 | issue = 1 | pages = 187–93 | date = Apr 2013 | pmid = 23375994 | doi = 10.1016/j.gene.2013.01.004 }}</ref> [[diabetic nephropathy]],<ref>{{cite journal | vauthors = Shoukry A, Shalaby SM, Abdelazim S, Abdelazim M, Ramadan A, Ismail MI, Fouad M | title = Endothelial nitric oxide synthase gene polymorphisms and the risk of diabetic nephropathy in type 2 diabetes mellitus | journal = Genetic Testing and Molecular Biomarkers | volume = 16 | issue = 6 | pages = 574–9 | date = Jun 2012 | pmid = 22313046 | doi = 10.1089/gtmb.2011.0218 }}</ref> and [[retinopathy]],<ref>{{cite journal | vauthors = Taverna MJ, Elgrably F, Selmi H, Selam JL, Slama G | title = The T-786C and C774T endothelial nitric oxide synthase gene polymorphisms independently affect the onset pattern of severe diabetic retinopathy | journal = Nitric Oxide | volume = 13 | issue = 1 | pages = 88–92 | date = Aug 2005 | pmid = 15890549 | doi = 10.1016/j.niox.2005.04.004 }}</ref> migraine,<ref name="ReferenceB">{{cite journal | vauthors = Eröz R, Bahadir A, Dikici S, Tasdemir S | title = Association of endothelial nitric oxide synthase gene polymorphisms (894G/T, -786T/C, G10T) and clinical findings in patients with migraine | journal = Neuromolecular Medicine | volume = 16 | issue = 3 | pages = 587–93 | date = Sep 2014 | pmid = 24845269 | doi = 10.1007/s12017-014-8311-0 | s2cid = 13894932 }}</ref> and erectile dysfunction.<ref>{{cite journal | vauthors = Safarinejad MR, Khoshdel A, Shekarchi B, Taghva A, Safarinejad S | title = Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects | journal = BJU International | volume = 107 | issue = 12 | pages = 1994–2001 | date = Jun 2011 | pmid = 20955262 | doi = 10.1111/j.1464-410X.2010.09755.x | s2cid = 27400035 | doi-access = free }}</ref> The presence of ‘Asp’ allele for the Glu298Asp polymorphism reduces eNOS activity,<ref>{{cite journal | vauthors = Joshi MS, Mineo C, Shaul PW, Bauer JA | title = Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear | journal = FASEB Journal | volume = 21 | issue = 11 | pages = 2655–63 | date = Sep 2007 | pmid = 17449720 | doi = 10.1096/fj.06-7088com | pmc = 7460804 }}</ref> and was associated with higher susceptibility to hypertension,<ref>{{cite journal | vauthors = Liu J, Wang L, Liu Y, Wang Z, Li M, Zhang B, Wang H, Liu K, Wen S | title = The association between endothelial nitric oxide synthase gene G894T polymorphism and hypertension in Han Chinese: a case-control study and an updated meta-analysis | journal = Annals of Human Biology | volume = 42 | issue = 2 | pages = 184–94 | date = Mar 2015 | pmid = 24846690 | doi = 10.3109/03014460.2014.911958 | s2cid = 8979107 }}</ref><ref>{{cite journal | vauthors = Pereira TV, Rudnicki M, Cheung BM, Baum L, Yamada Y, Oliveira PS, Pereira AC, Krieger JE | title = Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias | journal = Journal of Hypertension | volume = 25 | issue = 9 | pages = 1763–74 | date = Sep 2007 | pmid = 17762636 | doi = 10.1097/HJH.0b013e3281de740d | s2cid = 36745404 }}</ref> preeclampsia,<ref>{{cite journal | vauthors = Serrano NC, Casas JP, Díaz LA, Páez C, Mesa CM, Cifuentes R, Monterrosa A, Bautista A, Hawe E, Hingorani AD, Vallance P, López-Jaramillo P | title = Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study | journal = Hypertension | volume = 44 | issue = 5 | pages = 702–7 | date = Nov 2004 | pmid = 15364897 | doi = 10.1161/01.HYP.0000143483.66701.ec | doi-access = free }}</ref> diabetes mellitus,<ref name="ReferenceC">{{cite journal | vauthors = Jia Z, Zhang X, Kang S, Wu Y | title = Association of endothelial nitric oxide synthase gene polymorphisms with type 2 diabetes mellitus: a meta-analysis | journal = Endocrine Journal | volume = 60 | issue = 7 | pages = 893–901 | pmid = 23563728 | doi=10.1507/endocrj.ej12-0463 | year=2013| doi-access = free }}</ref> migraine,<ref name="ReferenceB"/> and erectile dysfunction.<ref>{{cite journal | vauthors = Lee YC, Huang SP, Liu CC, Yang YH, Yeh HC, Li WM, Wu WJ, Wang CJ, Juan YS, Huang CN, Hour TC, Chang CF, Huang CH | title = The association of eNOS G894T polymorphism with metabolic syndrome and erectile dysfunction | journal = The Journal of Sexual Medicine | volume = 9 | issue = 3 | pages = 837–43 | date = Mar 2012 | pmid = 22304542 | doi = 10.1111/j.1743-6109.2011.02588.x }}</ref><ref>{{cite journal | vauthors = Hermans MP, Ahn SA, Rousseau MF | title = eNOS [Glu298Asp] polymorphism, erectile function and ocular pressure in type 2 diabetes | journal = European Journal of Clinical Investigation | volume = 42 | issue = 7 | pages = 729–37 | date = Jul 2012 | pmid = 22224829 | doi = 10.1111/j.1365-2362.2011.02638.x | s2cid = 31746130 }}</ref> The VNTR in intron 4 affects eNOS expression,<ref>{{cite journal | vauthors = Zhang MX, Zhang C, Shen YH, Wang J, Li XN, Chen L, Zhang Y, Coselli JS, Wang XL | title = Effect of 27nt small RNA on endothelial nitric-oxide synthase expression | journal = Molecular Biology of the Cell | volume = 19 | issue = 9 | pages = 3997–4005 | date = Sep 2008 | pmid = 18614799 | doi = 10.1091/mbc.E07-11-1186 | pmc=2526692}}</ref> and the susceptibility to hypertension,<ref name="ReferenceA"/> preeclampsia,<ref name="Dai B 2013"/> obesity,<ref>{{cite journal | vauthors = Souza-Costa DC, Belo VA, Silva PS, Sertorio JT, Metzger IF, Lanna CM, Machado MA, Tanus-Santos JE | title = eNOS haplotype associated with hypertension in obese children and adolescents | journal = International Journal of Obesity | volume = 35 | issue = 3 | pages = 387–92 | date = Mar 2011 | pmid = 20661250 | doi = 10.1038/ijo.2010.146 | doi-access = free }}</ref> and diabetes mellitus.<ref name="ReferenceC"/> Growing evidence supports the association of diseases with NOS3 [[haplotype]]s (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.<ref>{{cite journal | vauthors = Crawford DC, Nickerson DA | title = Definition and clinical importance of haplotypes | journal = Annual Review of Medicine | volume = 56 | pages = 303–20 | pmid = 15660514 | doi = 10.1146/annurev.med.56.082103.104540 | year=2005}}</ref> Haplotypes including the SNPs g.-786T>C and Glu298Asp and the VNTR in intron 4 affected the susceptibility to hypertension,<ref>{{cite journal | vauthors = Sandrim VC, Coelho EB, Nobre F, Arado GM, Lanchote VL, Tanus-Santos JE | title = Susceptible and protective eNOS haplotypes in hypertensive black and white subjects | journal = Atherosclerosis | volume = 186 | issue = 2 | pages = 428–32 | date = Jun 2006 | pmid = 16168996 | doi = 10.1016/j.atherosclerosis.2005.08.003 }}</ref><ref>{{cite journal | vauthors = Sandrim VC, de Syllos RW, Lisboa HR, Tres GS, Tanus-Santos JE | title = Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus | journal = Atherosclerosis | volume = 189 | issue = 1 | pages = 241–6 | date = Nov 2006 | pmid = 16427644 | doi = 10.1016/j.atherosclerosis.2005.12.011 }}</ref><ref>{{cite journal | vauthors = Sandrim VC, Yugar-Toledo JC, Desta Z, Flockhart DA, Moreno H, Tanus-Santos JE | title = Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy | journal = Journal of Hypertension | volume = 24 | issue = 12 | pages = 2393–7 | date = Dec 2006 | pmid = 17082721 | doi = 10.1097/01.hjh.0000251899.47626.4f | s2cid = 20666422 }}</ref><ref>{{cite journal | vauthors = Vasconcellos V, Lacchini R, Jacob-Ferreira AL, Sales ML, Ferreira-Sae MC, Schreiber R, Nadruz W, Tanus-Santos JE | title = Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy | journal = DNA and Cell Biology | volume = 29 | issue = 4 | pages = 171–6 | date = Apr 2010 | pmid = 20070154 | doi = 10.1089/dna.2009.0955 }}</ref> preeclampsia,<ref>{{cite journal | vauthors = Sandrim VC, Palei AC, Sertorio JT, Cavalli RC, Duarte G, Tanus-Santos JE | title = Effects of eNOS polymorphisms on nitric oxide formation in healthy pregnancy and in pre-eclampsia | journal = Molecular Human Reproduction | volume = 16 | issue = 7 | pages = 506–10 | date = Jul 2010 | pmid = 20457799 | doi = 10.1093/molehr/gaq030 | doi-access = free }}</ref> and hypertension in diabetic subjects.<ref>{{cite journal | vauthors = de Syllos RW, Sandrim VC, Lisboa HR, Tres GS, Tanus-Santos JE | title = Endothelial nitric oxide synthase genotype and haplotype are not associated with diabetic retinopathy in diabetes type 2 patients | journal = Nitric Oxide | volume = 15 | issue = 4 | pages = 417–22 | date = Dec 2006 | pmid = 16581274 | doi = 10.1016/j.niox.2006.02.002 }}</ref>
NOS3 variants may also affect the responses to drugs that affect NO signaling, such as statins, angiotensin-converting enzyme inhibitors ([[ACE inhibitor|ACEi]]) and phosphodiesterase type 5 (PDE-5) inhibitors ([[PDE5 inhibitor|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.<ref>{{cite journal | vauthors = Nagassaki S, Sertório JT, Metzger IF, Bem AF, Rocha JB, Tanus-Santos JE | title = eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite | journal = Free Radical Biology & Medicine | volume = 41 | issue = 7 | pages = 1044–9 | date = Oct 2006 | pmid = 16962929 | doi = 10.1016/j.freeradbiomed.2006.04.026 }}</ref><ref>{{cite journal | vauthors = Andrade VL, Sertório JT, Eleuterio NM, Tanus-Santos JE, Fernandes KS, Sandrim VC | title = Simvastatin treatment increases nitrite levels in obese women: modulation by T(-786)C polymorphism of eNOS | journal = Nitric Oxide | volume = 33 | pages = 83–7 | date = Sep 2013 | pmid = 23876348 | doi = 10.1016/j.niox.2013.07.005 | hdl = 11449/76257 | hdl-access = free }}</ref> Hypertensive patients carrying the TC/CC genotypes and the C allele for the g.-786T>C polymorphism showed better antihypertensive responses to ACEi [[enalapril]].<ref>{{cite journal | vauthors = Silva PS, Fontana V, Luizon MR, Lacchini R, Silva WA, Biagi C, Tanus-Santos JE | title = eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril | journal = European Journal of Clinical Pharmacology | volume = 69 | issue = 2 | pages = 167–77 | date = Feb 2013 | pmid = 22706620 | doi = 10.1007/s00228-012-1326-2 | s2cid = 2063573 }}</ref> Likewise, patients with erectile dysfunction carrying the C allele for g.-786T>C polymorphism showed better responses to PDE-5 inhibitor [[sildenafil]].<ref name="Muniz JJ 2011">{{cite journal | vauthors = Muniz JJ, Lacchini R, Rinaldi TO, Nobre YT, Cologna AJ, Martins AC, Tanus-Santos JE | title = Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction | journal = The Pharmacogenomics Journal | volume = 13 | issue = 2 | pages = 189–96 | date = Apr 2013 | pmid = 22064666 | doi = 10.1038/tpj.2011.49 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lacchini R, Tanus-Santos JE | title = Pharmacogenetics of erectile dysfunction: navigating into uncharted waters | journal = Pharmacogenomics | volume = 15 | issue = 11 | pages = 1519–38 | date = Aug 2014 | pmid = 25303302 | doi = 10.2217/pgs.14.110 }}</ref> 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.<ref name="Muniz JJ 2011"/>

==Notes==
{{Academic-written review|Q=Q38597218}}

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = de la Monte SM, Lu BX, Sohn YK, Etienne D, Kraft J, Ganju N, Wands JR | title = Aberrant expression of nitric oxide synthase III in Alzheimer's disease: relevance to cerebral vasculopathy and neurodegeneration | journal = Neurobiology of Aging | volume = 21 | issue = 2 | pages = 309–19 | year = 2000 | pmid = 10867216 | doi = 10.1016/S0197-4580(99)00108-6 | s2cid = 34155727 }}
* {{cite journal | vauthors = Shaul PW | title = Regulation of endothelial nitric oxide synthase: location, location, location | journal = Annual Review of Physiology | volume = 64 | pages = 749–74 | year = 2002 | pmid = 11826287 | doi = 10.1146/annurev.physiol.64.081501.155952 }}
* {{cite journal | vauthors = Wu KK | title = Regulation of endothelial nitric oxide synthase activity and gene expression | journal = Annals of the New York Academy of Sciences | volume = 962 | issue =  1| pages = 122–30 | date = May 2002 | pmid = 12076969 | doi = 10.1111/j.1749-6632.2002.tb04062.x | bibcode = 2002NYASA.962..122W | s2cid = 20537144 }}
* {{cite journal | vauthors = Alp NJ, Channon KM | title = Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 3 | pages = 413–20 | date = Mar 2004 | pmid = 14656731 | doi = 10.1161/01.ATV.0000110785.96039.f6 | doi-access = free }}
* {{cite journal | vauthors = Tai SC, Robb GB, Marsden PA | title = Endothelial nitric oxide synthase: a new paradigm for gene regulation in the injured blood vessel | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 3 | pages = 405–12 | date = Mar 2004 | pmid = 14656742 | doi = 10.1161/01.ATV.0000109171.50229.33 | doi-access = free }}
* {{cite journal | vauthors = Kawashima S, Yokoyama M | title = Dysfunction of endothelial nitric oxide synthase and atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 6 | pages = 998–1005 | date = Jun 2004 | pmid = 15001455 | doi = 10.1161/01.ATV.0000125114.88079.96 | doi-access = free }}
* {{cite journal | vauthors = Duda DG, Fukumura D, Jain RK | title = Role of eNOS in neovascularization: NO for endothelial progenitor cells | journal = Trends in Molecular Medicine | volume = 10 | issue = 4 | pages = 143–5 | date = Apr 2004 | pmid = 15162796 | doi = 10.1016/j.molmed.2004.02.001 }}
{{refend}}

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