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Wikipedia

Endothelial NOS

January 01, 1970

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.[5] This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes.[6][7] The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain[8] and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases.[9] eNOS is primarily responsible for the generation of NO in the vascular endothelium,[10] 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.[11] NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation.[12] Therefore, a functional eNOS is essential for a healthy cardiovascular system.

NOS3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNOS3, ECNOS, eNOS, nitric oxide synthase 3
External IDsOMIM: 163729 MGI: 97362 HomoloGene: 504 GeneCards: NOS3
Orthologs
SpeciesHumanMouse
Entrez

4846

18127

Ensembl

ENSG00000164867

ENSMUSG00000028978

UniProt

P29474

P70313

RefSeq (mRNA)

NM_000603
NM_001160109
NM_001160110
NM_001160111

NM_008713

RefSeq (protein)

NP_000594
NP_001153581
NP_001153582
NP_001153583

NP_032739

Location (UCSC)Chr 7: 150.99 – 151.01 MbChr 5: 24.57 – 24.59 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and catalytic activities edit

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.[13] The reductase domain is linked to the oxidase domain by a calmodulin-binding sequence.[14] 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.[15][16] The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO.[17] In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled.[18] In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.[19][20]

Function edit

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).[21] cGMP, in turn, activates protein kinase G (PKG), which promotes multiple phosphorylation of cellular targets lowering cellular Ca2+ concentrations and promoting vascular relaxation.[22] 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.[23][24] NO also has antithrombotic effects that result of its diffusion across platelet membrane and sGC activation, resulting in inhibition of platelet aggregation.[25] 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.[26] 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.[27] 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.[28]

Regulation edit

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.[29] Posttranscriptionally, eNOS is regulated by modifications of the primary transcript, mRNA stability, subcellular localization, and nucleocytoplasmatic transport.[30] 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.[31] With the binding of eNOS to caveolae, the enzyme is inactivated due to the strong and direct interaction of eNOS with caveolin-1.[32] 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. [33] Moreover, eNOS activation is dynamically regulated by multiple phosphorylation sites at tyrosine, serine, and threonine residues.[13]

Clinical significance edit

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.[34] The C allele for the g.-786T>C polymorphism, which results in reduced eNOS expression and NO production,[35] was associated with increased risk for hypertension,[36] preeclampsia,[37] diabetic nephropathy,[38] and retinopathy,[39] migraine,[40] and erectile dysfunction.[41] The presence of ‘Asp’ allele for the Glu298Asp polymorphism reduces eNOS activity,[42] and was associated with higher susceptibility to hypertension,[43][44] preeclampsia,[45] diabetes mellitus,[46] migraine,[40] and erectile dysfunction.[47][48] The VNTR in intron 4 affects eNOS expression,[49] and the susceptibility to hypertension,[36] preeclampsia,[37] obesity,[50] and diabetes mellitus.[46] 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.[51] Haplotypes including the SNPs g.-786T>C and Glu298Asp and the VNTR in intron 4 affected the susceptibility to hypertension,[52][53][54][55] preeclampsia,[56] and hypertension in diabetic subjects.[57] 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.[58][59] Hypertensive patients carrying the TC/CC genotypes and the C allele for the g.-786T>C polymorphism showed better antihypertensive responses to ACEi enalapril.[60] Likewise, patients with erectile dysfunction carrying the C allele for g.-786T>C polymorphism showed better responses to PDE-5 inhibitor sildenafil.[61][62] 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.[61]

Notes edit

References edit

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Further reading edit

  • de la Monte SM, Lu BX, Sohn YK, Etienne D, Kraft J, Ganju N, Wands JR (2000). "Aberrant expression of nitric oxide synthase III in Alzheimer's disease: relevance to cerebral vasculopathy and neurodegeneration". Neurobiology of Aging. 21 (2): 309–19. doi:10.1016/S0197-4580(99)00108-6. PMID 10867216. S2CID 34155727.
  • Shaul PW (2002). "Regulation of endothelial nitric oxide synthase: location, location, location". Annual Review of Physiology. 64: 749–74. doi:10.1146/annurev.physiol.64.081501.155952. PMID 11826287.
  • Wu KK (May 2002). "Regulation of endothelial nitric oxide synthase activity and gene expression". Annals of the New York Academy of Sciences. 962 (1): 122–30. Bibcode:2002NYASA.962..122W. doi:10.1111/j.1749-6632.2002.tb04062.x. PMID 12076969. S2CID 20537144.
  • Alp NJ, Channon KM (Mar 2004). "Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (3): 413–20. doi:10.1161/01.ATV.0000110785.96039.f6. PMID 14656731.
  • Tai SC, Robb GB, Marsden PA (Mar 2004). "Endothelial nitric oxide synthase: a new paradigm for gene regulation in the injured blood vessel". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (3): 405–12. doi:10.1161/01.ATV.0000109171.50229.33. PMID 14656742.
  • Kawashima S, Yokoyama M (Jun 2004). "Dysfunction of endothelial nitric oxide synthase and atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (6): 998–1005. doi:10.1161/01.ATV.0000125114.88079.96. PMID 15001455.
  • Duda DG, Fukumura D, Jain RK (Apr 2004). "Role of eNOS in neovascularization: NO for endothelial progenitor cells". Trends in Molecular Medicine. 10 (4): 143–5. doi:10.1016/j.molmed.2004.02.001. PMID 15162796.

January 01, 1970
endothelial, enos, also, known, nitric, oxide, synthase, nos3, constitutive, cnos, enzyme, that, humans, encoded, nos3, gene, located, 7q35, 7q36, region, chromosome, this, enzyme, three, isoforms, that, synthesize, nitric, oxide, small, gaseous, lipophilic, m. 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 5 This enzyme is one of three isoforms that synthesize nitric oxide NO a small gaseous and lipophilic molecule that participates in several biological processes 6 7 The other isoforms include neuronal nitric oxide synthase nNOS which is constitutively expressed in specific neurons of the brain 8 and inducible nitric oxide synthase iNOS whose expression is typically induced in inflammatory diseases 9 eNOS is primarily responsible for the generation of NO in the vascular endothelium 10 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 11 NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone cellular proliferation leukocyte adhesion and platelet aggregation 12 Therefore a functional eNOS is essential for a healthy cardiovascular system NOS3Available structuresPDBOrtholog search PDBe RCSBList of PDB id codes1M9J 1M9K 1M9M 1M9Q 1M9R 1NIW 2LL7 3EAH 3NOS 2MG5 4D1O 4D1PIdentifiersAliasesNOS3 ECNOS eNOS nitric oxide synthase 3External IDsOMIM 163729 MGI 97362 HomoloGene 504 GeneCards NOS3Gene location Human Chr Chromosome 7 human 1 Band7q36 1Start150 991 017 bp 1 End151 014 588 bp 1 Gene location Mouse Chr Chromosome 5 mouse 2 Band5 A3 5 11 32 cMStart24 569 808 bp 2 End24 589 472 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inspleenupper lobe of left lungleft uterine tubeleft ventricleright lobe of thyroid glandleft coronary arteryright coronary arterygastric mucosatibial nerveright lungTop expressed inright ventriclesubcutaneous adipose tissuewhite adipose tissueendocardial cushionbrown adipose tissuedigastric muscleinterventricular septumatriumsternocleidomastoid muscleatrioventricular valveMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionFMN binding actin monomer binding flavin adenine dinucleotide binding scaffold protein binding arginine binding tetrahydrobiopterin binding metal ion binding calmodulin binding protein binding heme binding NADP binding oxidoreductase activity cadmium ion binding nitric oxide synthase activity NADPH hemoprotein reductase activityCellular componentcytoplasm endocytic vesicle membrane cytosol Golgi apparatus membrane Golgi membrane plasma membrane caveola cytoskeleton nucleus vesicle membraneBiological processnegative regulation of muscle hyperplasia ovulation from ovarian follicle positive regulation of guanylate cyclase activity nitric oxide biosynthetic process regulation of systemic arterial blood pressure by endothelin regulation of sodium ion transport lung development negative regulation of blood pressure removal of superoxide radicals regulation of nitric oxide synthase activity mitochondrion organization response to heat in utero embryonic development negative regulation of hydrolase activity cell redox homeostasis arginine catabolic process response to fluid shear stress regulation of blood pressure negative regulation of platelet activation blood vessel remodeling negative regulation of extrinsic apoptotic signaling pathway via death domain receptors angiogenesis negative regulation of potassium ion transport nitric oxide mediated signal transduction negative regulation of calcium ion transport smooth muscle hyperplasia regulation of the force of heart contraction by chemical signal endothelial cell migration lipopolysaccharide mediated signaling pathway negative regulation of cell population proliferation vasodilation positive regulation of blood vessel endothelial cell migration positive regulation of angiogenesis aortic valve morphogenesis pulmonary valve morphogenesis endocardial cushion morphogenesis positive regulation of gene expression homeostasis of number of cells within a tissue ventricular septum morphogenesis negative regulation of biomineral tissue development response to hormone response to lipopolysaccharide regulation of nervous system process positive regulation of Notch signaling pathwaySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez484618127EnsemblENSG00000164867ENSMUSG00000028978UniProtP29474P70313RefSeq mRNA NM 000603NM 001160109NM 001160110NM 001160111NM 008713RefSeq protein NP 000594NP 001153581NP 001153582NP 001153583NP 032739Location UCSC Chr 7 150 99 151 01 MbChr 5 24 57 24 59 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Structure and catalytic activities 2 Function 3 Regulation 4 Clinical significance 5 Notes 6 References 7 Further readingStructure and catalytic activities editeNOS 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 13 The reductase domain is linked to the oxidase domain by a calmodulin binding sequence 14 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 15 16 The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO 17 In the absence of this cofactor eNOS shifts from a dimeric to a monomeric form thus becoming uncoupled 18 In this conformation instead of synthesizing NO eNOS produces superoxide anion a highly reactive free radical with deleterious consequences to the cardiovascular system 19 20 Function editeNOS 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 21 cGMP in turn activates protein kinase G PKG which promotes multiple phosphorylation of cellular targets lowering cellular Ca2 concentrations and promoting vascular relaxation 22 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 23 24 NO also has antithrombotic effects that result of its diffusion across platelet membrane and sGC activation resulting in inhibition of platelet aggregation 25 Moreover NO affects leukocyte adhesion to the vascular endothelium by inhibiting the nuclear factor kappa B NF kB which induces vascular endothelial expression of chemokines and adhesion molecules 26 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 27 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 28 Regulation editeNOS 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 29 Posttranscriptionally eNOS is regulated by modifications of the primary transcript mRNA stability subcellular localization and nucleocytoplasmatic transport 30 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 31 With the binding of eNOS to caveolae the enzyme is inactivated due to the strong and direct interaction of eNOS with caveolin 1 32 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 33 Moreover eNOS activation is dynamically regulated by multiple phosphorylation sites at tyrosine serine and threonine residues 13 Clinical significance editImpaired 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 gt 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 34 The C allele for the g 786T gt C polymorphism which results in reduced eNOS expression and NO production 35 was associated with increased risk for hypertension 36 preeclampsia 37 diabetic nephropathy 38 and retinopathy 39 migraine 40 and erectile dysfunction 41 The presence of Asp allele for the Glu298Asp polymorphism reduces eNOS activity 42 and was associated with higher susceptibility to hypertension 43 44 preeclampsia 45 diabetes mellitus 46 migraine 40 and erectile dysfunction 47 48 The VNTR in intron 4 affects eNOS expression 49 and the susceptibility to hypertension 36 preeclampsia 37 obesity 50 and diabetes mellitus 46 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 51 Haplotypes including the SNPs g 786T gt C and Glu298Asp and the VNTR in intron 4 affected the susceptibility to hypertension 52 53 54 55 preeclampsia 56 and hypertension in diabetic subjects 57 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 gt C polymorphism than in TT carriers 58 59 Hypertensive patients carrying the TC CC genotypes and the C allele for the g 786T gt C polymorphism showed better antihypertensive responses to ACEi enalapril 60 Likewise patients with erectile dysfunction carrying the C allele for g 786T gt C polymorphism showed better responses to PDE 5 inhibitor sildenafil 61 62 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 gt C NOS3 polymorphism thus attenuating the cardiovascular risk In addition to analysis of genetic polymorphisms individually haplotypes including the SNPs g 786T gt C and Glu298Asp and the VNTR in intron 4 were shown to affect the responses to sildenafil in patients with erectile dysfunction 61 Notes editThe 2015 version of this article was updated by an external expert under a dual publication model The corresponding academic peer reviewed article was published in Gene and can be cited as Gustavo H Oliveira Paula Riccardo Lacchini Jose E Tanus Santos 28 September 2015 Endothelial nitric oxide synthase From biochemistry and gene structure to clinical implications of NOS3 polymorphisms Gene Gene Wiki Review Series 575 2 Pt 3 584 599 doi 10 1016 J GENE 2015 09 061 ISSN 0378 1119 PMC 6728140 PMID 26428312 Wikidata Q38597218 References edit a b c GRCh38 Ensembl release 89 ENSG00000164867 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000028978 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Marsden PA Schappert KT Chen HS Flowers M Sundell CL Wilcox JN Lamas S Michel T August 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Marsden PA Jan 2006 Endothelial nitric oxide synthase insight into cell specific gene regulation in the vascular endothelium Cellular and Molecular Life Sciences 63 2 144 62 doi 10 1007 s00018 005 5421 8 PMID 16416260 S2CID 22111996 Sumpio BE Riley JT Dardik A Dec 2002 Cells in focus endothelial cell The International Journal of Biochemistry amp Cell Biology 34 12 1508 12 doi 10 1016 s1357 2725 02 00075 4 PMID 12379270 Forstermann U Munzel T Apr 2006 Endothelial nitric oxide synthase in vascular disease from marvel to menace Circulation 113 13 1708 14 doi 10 1161 CIRCULATIONAHA 105 602532 PMID 16585403 a b Qian J Fulton D 2013 Post translational regulation of endothelial nitric oxide synthase in vascular endothelium Frontiers in Physiology 4 347 doi 10 3389 fphys 2013 00347 PMC 3861784 PMID 24379783 Alderton WK Cooper CE Knowles RG Aug 2001 Nitric oxide synthases structure function and inhibition The Biochemical Journal 357 Pt 3 593 615 doi 10 1042 bj3570593 PMC 1221991 PMID 11463332 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of Biological Chemistry 267 25 18148 53 doi 10 1016 S0021 9258 19 37165 0 hdl 2437 120319 PMID 1517245 Karantzoulis Fegaras F Antoniou H Lai SL Kulkarni G D Abreo C Wong GK Miller TL Chan Y Atkins J Wang Y Marsden PA Jan 1999 Characterization of the human endothelial nitric oxide synthase promoter The Journal of Biological Chemistry 274 5 3076 93 doi 10 1074 jbc 274 5 3076 PMID 9915847 Searles CD Nov 2006 Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression American Journal of Physiology Cell Physiology 291 5 C803 16 doi 10 1152 ajpcell 00457 2005 PMID 16738003 Lisanti MP Scherer PE Tang Z Sargiacomo M Jul 1994 Caveolae caveolin and caveolin rich membrane domains a signalling hypothesis Trends in Cell Biology 4 7 231 5 doi 10 1016 0962 8924 94 90114 7 PMID 14731661 Ju H Zou R Venema VJ Venema RC Jul 1997 Direct interaction of endothelial nitric oxide synthase and caveolin 1 inhibits synthase activity The Journal of Biological Chemistry 272 30 18522 5 doi 10 1074 jbc 272 30 18522 PMID 9228013 Collins B Davis M Hancock J Parton R Jun 2012 Structure based Reassessment of the Caveolin Signaling Model Do Caveolae Regulate Signaling Through Caveolin Protein Interactions Dev Cell 23 1 11 20 doi 10 1016 j devcel 2012 06 012 PMC 3427029 PMID 3427029 Lacchini R Silva PS Tanus Santos JE May 2010 A pharmacogenetics based approach to reduce cardiovascular mortality with the prophylactic use of statins Basic amp Clinical Pharmacology amp Toxicology 106 5 357 61 doi 10 1111 j 1742 7843 2010 00551 x PMID 20210789 Nakayama M Yasue H Yoshimura M Shimasaki Y Kugiyama K Ogawa H Motoyama T Saito Y Ogawa Y Miyamoto Y Nakao K Jun 1999 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 doi 10 1161 01 cir 99 22 2864 PMID 10359729 a b Niu W Qi Y 2011 An updated meta analysis of endothelial nitric oxide synthase gene three well characterized polymorphisms with hypertension PLOS ONE 6 9 e24266 Bibcode 2011PLoSO 624266N doi 10 1371 journal pone 0024266 PMC 3166328 PMID 21912683 a b Dai B Liu T Zhang B Zhang X Wang Z Apr 2013 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 doi 10 1016 j gene 2013 01 004 PMID 23375994 Shoukry A Shalaby SM Abdelazim S Abdelazim M Ramadan A Ismail MI Fouad M Jun 2012 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 doi 10 1089 gtmb 2011 0218 PMID 22313046 Taverna MJ Elgrably F Selmi H Selam JL Slama G Aug 2005 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 doi 10 1016 j niox 2005 04 004 PMID 15890549 a b Eroz R Bahadir A Dikici S Tasdemir S Sep 2014 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Chinese a case control study and an updated meta analysis Annals of Human Biology 42 2 184 94 doi 10 3109 03014460 2014 911958 PMID 24846690 S2CID 8979107 Pereira TV Rudnicki M Cheung BM Baum L Yamada Y Oliveira PS Pereira AC Krieger JE Sep 2007 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 doi 10 1097 HJH 0b013e3281de740d PMID 17762636 S2CID 36745404 Serrano NC Casas JP Diaz LA Paez C Mesa CM Cifuentes R Monterrosa A Bautista A Hawe E Hingorani AD Vallance P Lopez Jaramillo P Nov 2004 Endothelial NO synthase genotype and risk of preeclampsia a multicenter case control study Hypertension 44 5 702 7 doi 10 1161 01 HYP 0000143483 66701 ec PMID 15364897 a b Jia Z Zhang X Kang S Wu Y 2013 Association of endothelial nitric oxide synthase gene polymorphisms with type 2 diabetes mellitus a meta analysis Endocrine Journal 60 7 893 901 doi 10 1507 endocrj ej12 0463 PMID 23563728 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 Mar 2012 The association of eNOS G894T polymorphism with metabolic syndrome and erectile dysfunction The Journal of Sexual Medicine 9 3 837 43 doi 10 1111 j 1743 6109 2011 02588 x PMID 22304542 Hermans MP Ahn SA Rousseau MF Jul 2012 eNOS Glu298Asp polymorphism erectile function and ocular pressure in type 2 diabetes European Journal of Clinical Investigation 42 7 729 37 doi 10 1111 j 1365 2362 2011 02638 x PMID 22224829 S2CID 31746130 Zhang MX Zhang C Shen YH Wang J Li XN Chen L Zhang Y Coselli JS Wang XL Sep 2008 Effect of 27nt small RNA on endothelial nitric oxide synthase expression Molecular Biology of the Cell 19 9 3997 4005 doi 10 1091 mbc E07 11 1186 PMC 2526692 PMID 18614799 Souza Costa DC Belo VA Silva PS Sertorio JT Metzger IF Lanna CM Machado MA Tanus Santos JE Mar 2011 eNOS haplotype associated with hypertension in obese children and adolescents International Journal of Obesity 35 3 387 92 doi 10 1038 ijo 2010 146 PMID 20661250 Crawford DC Nickerson DA 2005 Definition and clinical importance of haplotypes Annual Review of Medicine 56 303 20 doi 10 1146 annurev med 56 082103 104540 PMID 15660514 Sandrim VC Coelho EB Nobre F Arado GM Lanchote VL Tanus Santos JE Jun 2006 Susceptible and protective eNOS haplotypes in hypertensive black and white subjects Atherosclerosis 186 2 428 32 doi 10 1016 j atherosclerosis 2005 08 003 PMID 16168996 Sandrim VC de Syllos RW Lisboa HR Tres GS Tanus Santos JE Nov 2006 Endothelial nitric oxide synthase haplotypes affect the susceptibility to hypertension in patients with type 2 diabetes mellitus Atherosclerosis 189 1 241 6 doi 10 1016 j atherosclerosis 2005 12 011 PMID 16427644 Sandrim VC Yugar Toledo JC Desta Z Flockhart DA Moreno H Tanus Santos JE Dec 2006 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 doi 10 1097 01 hjh 0000251899 47626 4f PMID 17082721 S2CID 20666422 Vasconcellos V Lacchini R Jacob Ferreira AL Sales ML Ferreira Sae MC Schreiber R Nadruz W Tanus Santos JE Apr 2010 Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy DNA and Cell Biology 29 4 171 6 doi 10 1089 dna 2009 0955 PMID 20070154 Sandrim VC Palei AC Sertorio JT Cavalli RC Duarte G Tanus Santos JE Jul 2010 Effects of eNOS polymorphisms on nitric oxide formation in healthy pregnancy and in pre eclampsia Molecular Human Reproduction 16 7 506 10 doi 10 1093 molehr gaq030 PMID 20457799 de Syllos RW Sandrim VC Lisboa HR Tres GS Tanus Santos JE Dec 2006 Endothelial nitric oxide synthase genotype and haplotype are not associated with diabetic retinopathy in diabetes type 2 patients Nitric Oxide 15 4 417 22 doi 10 1016 j niox 2006 02 002 PMID 16581274 Nagassaki S Sertorio JT Metzger IF Bem AF Rocha JB Tanus Santos JE Oct 2006 eNOS gene T 786C polymorphism modulates atorvastatin induced increase in blood nitrite Free Radical Biology amp Medicine 41 7 1044 9 doi 10 1016 j freeradbiomed 2006 04 026 PMID 16962929 Andrade VL Sertorio JT Eleuterio NM Tanus Santos JE Fernandes KS Sandrim VC Sep 2013 Simvastatin treatment increases nitrite levels in obese women modulation by T 786 C polymorphism of eNOS Nitric Oxide 33 83 7 doi 10 1016 j niox 2013 07 005 hdl 11449 76257 PMID 23876348 Silva PS Fontana V Luizon MR Lacchini R Silva WA Biagi C Tanus Santos JE Feb 2013 eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril European Journal of Clinical Pharmacology 69 2 167 77 doi 10 1007 s00228 012 1326 2 PMID 22706620 S2CID 2063573 a b Muniz JJ Lacchini R Rinaldi TO Nobre YT Cologna AJ Martins AC Tanus Santos JE Apr 2013 Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction The Pharmacogenomics Journal 13 2 189 96 doi 10 1038 tpj 2011 49 PMID 22064666 Lacchini R Tanus Santos JE Aug 2014 Pharmacogenetics of erectile dysfunction navigating into uncharted waters Pharmacogenomics 15 11 1519 38 doi 10 2217 pgs 14 110 PMID 25303302 Further reading editde la Monte SM Lu BX Sohn YK Etienne D Kraft J Ganju N Wands JR 2000 Aberrant expression of nitric oxide synthase III in Alzheimer s disease relevance to cerebral vasculopathy and neurodegeneration Neurobiology of Aging 21 2 309 19 doi 10 1016 S0197 4580 99 00108 6 PMID 10867216 S2CID 34155727 Shaul PW 2002 Regulation of endothelial nitric oxide synthase location location location Annual Review of Physiology 64 749 74 doi 10 1146 annurev physiol 64 081501 155952 PMID 11826287 Wu KK May 2002 Regulation of endothelial nitric oxide synthase activity and gene expression Annals of the New York Academy of Sciences 962 1 122 30 Bibcode 2002NYASA 962 122W doi 10 1111 j 1749 6632 2002 tb04062 x PMID 12076969 S2CID 20537144 Alp NJ Channon KM Mar 2004 Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease Arteriosclerosis Thrombosis and Vascular Biology 24 3 413 20 doi 10 1161 01 ATV 0000110785 96039 f6 PMID 14656731 Tai SC Robb GB Marsden PA Mar 2004 Endothelial nitric oxide synthase a new paradigm for gene regulation in the injured blood vessel Arteriosclerosis Thrombosis and Vascular Biology 24 3 405 12 doi 10 1161 01 ATV 0000109171 50229 33 PMID 14656742 Kawashima S Yokoyama M Jun 2004 Dysfunction of endothelial nitric oxide synthase and atherosclerosis Arteriosclerosis Thrombosis and Vascular Biology 24 6 998 1005 doi 10 1161 01 ATV 0000125114 88079 96 PMID 15001455 Duda DG Fukumura D Jain RK Apr 2004 Role of eNOS in neovascularization NO for endothelial progenitor cells Trends in Molecular Medicine 10 4 143 5 doi 10 1016 j molmed 2004 02 001 PMID 15162796 Portal nbsp Biology Retrieved from https en wikipedia org w index php title Endothelial NOS amp oldid 1215890394, wikipedia, wiki, book, 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