Abstract The endothelial isoform of nitric-oxide synthase (eNOS) is regulated by a complex pattern of post-translational modifications. Although once considered a constitutive “housekeeping gene,” evidence suggests that expression of the eNOS gene may be activated via transcriptional mechanisms. 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. Abnormalities in NO production by the vascular endothelium result in endothelial dysfunction, which occurs in hypertension, diabetes, aging, and as a prelude to atherosclerosis. Increasing endothelial nitric oxide synthase may help with hypertension for some people. [18] In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system. The corresponding, negative regulation of muscle hyperplasia, positive regulation of guanylate cyclase activity, regulation of systemic arterial blood pressure by endothelin, regulation of nitric-oxide synthase activity, negative regulation of hydrolase activity, negative regulation of platelet activation, negative regulation of extrinsic apoptotic signaling pathway via death domain receptors, negative regulation of potassium ion transport, nitric oxide mediated signal transduction, negative regulation of calcium ion transport, regulation of the force of heart contraction by chemical signal, lipopolysaccharide-mediated signaling pathway, negative regulation of cell proliferation, positive regulation of blood vessel diameter, positive regulation of blood vessel endothelial cell migration, homeostasis of number of cells within a tissue, negative regulation of biomineral tissue development, regulation of neurological system process, positive regulation of Notch signaling pathway, nicotinamide adenine dinucleotide phosphate, "Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms", GRCh38: Ensembl release 89: ENSG00000164867, GRCm38: Ensembl release 89: ENSMUSG00000028978, "Exploring vascular benefits of endothelium-derived nitric oxide", "Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease", "Nitric oxide synthases: regulation and function", "Endothelial nitric oxide synthase in vascular disease: from marvel to menace", "Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium", "Nitric oxide synthases: structure, function and inhibition", "Free radical production by dysfunctional eNOS", 10.1146/annurev.pharmtox.44.101802.121844, "Subcellular localization of oxidants and redox modulation of endothelial nitric oxide synthase", "Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation", "New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases", "Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training", "Characterization of the human endothelial nitric-oxide synthase promoter", "Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity", "T-786→C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm", "An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension", "Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear", "Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study", "Association of endothelial nitric oxide synthase gene polymorphisms with type 2 diabetes mellitus: a meta-analysis", "Effect of 27nt small RNA on endothelial nitric-oxide synthase expression", "eNOS haplotype associated with hypertension in obese children and adolescents", "Effects of eNOS polymorphisms on nitric oxide formation in healthy pregnancy and in pre-eclampsia", "Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction", "Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease", "Endothelial nitric oxide synthase: a new paradigm for gene regulation in the injured blood vessel", "Dysfunction of endothelial nitric oxide synthase and atherosclerosis", Ethylene glycol dinitrate (EGDN; nitroglycol), Naproxcinod (nitronaproxen; AZD-3582, HCT-3012), Nitroglycerin (glyceryl trinitrate (GTN)), Amyl nitrite (isoamyl nitrite, isopentyl nitrite), Isobutyl nitrite (2-methylpropyl nitrite), Methylamine hexamethylene methylamine/NO (MAHMA/NO), N-Acetyl-N-acetoxy-4-chlorobenzenesulfonamide, https://en.wikipedia.org/w/index.php?title=Endothelial_NOS&oldid=992001617, Wikipedia articles with corresponding academic peer reviewed articles, Wikipedia articles with corresponding articles published in Gene, Creative Commons Attribution-ShareAlike License, cGMP preferring PDE inhibitors (e.g., sildenafil, paraxanthine, tadalafil), This page was last edited on 2 December 2020, at 23:30. [14] [45] Growing evidence supports the association of diseases with NOS3 haplotypes (combination of alleles in close proximity, within a DNA block). Endothelial nitric oxide synthase is predominantly a constitutive isoform expressed in normal adult bone. The gene coding for eNOS is … ). The concept that endothelium-derived nitric oxide (NO) is an important molecule in prevention of (progression of) atherosclerosis has been well established. 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. [13], Impaired NO production is involved in the pathogenesis of several diseases such as hypertension, preeclampsia, diabetes mellitus, obesity, erectile dysfunction, and migraine. [60], 1d0c: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 3-BROMO-7-NITROINDAZOLE (H4B FREE), 1d0o: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 3-BROMO-7-NITROINDAZOLE (H4B PRESENT), 1d1v: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH S-ETHYL-N-PHENYL-ISOTHIOUREA (H4B BOUND), 1d1w: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 2-AMINOTHIAZOLINE (H4B BOUND), 1d1x: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 1,4-PBITU (H4B BOUND), 1d1y: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 1,3-PBITU (H4B FREE), 1dm6: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH N-(4-CHLOROPHENYL)-N'-HYDROXYGUANIDINE (H4B FREE), 1dm7: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH HOMOARGININE (H4B FREE), 1dm8: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 1,2,4-TRIAZOLE-CARBOXAMIDINE (H4B BOUND), 1dmi: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 6S-H4B, 1dmj: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 5,6-CYCLIC-TETRAHYDROPTERIDINE, 1dmk: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE, 1ed4: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH IPITU (H4B FREE), 1ed5: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH NNA(H4B FREE), 1ed6: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH L-NIO (H4B FREE), 1foi: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 1400W(H4B-FREE), 1foj: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 7-NITROINDAZOLE-2-CARBOXAMIDINE (H4B PRESENT), 1fol: REDUCED BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH L-ARG(H4B-FREE), 1foo: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH L-ARG AND NO(H4B-FREE), 1fop: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH L-ARG AND NO(H4B-BOUND), 1i83: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH N1,N14-BIS((S-METHYL)ISOTHIOUREIDO)TETRADECANE (H4B FREE), 1m9j: human endothelial nitric oxide synthase with chlorzoxazone bound, 1m9k: Human Endothelial Nitric Oxide Synthase with 7-Nitroindazole Bound, 1m9m: human endothelial nitric oxide synthase with 6-nitroindazole bound, 1m9q: human endothelial nitric oxide synthase with 5-nitroindazole bound, 1m9r: human endothelial nitric oxide synthase with 3-Bromo-7-Nitroindazole bound, 1nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE, 1p6l: Bovine endothelial NOS heme domain with L-N(omega)-nitroarginine-2,4-L-diaminobutyric amide bound, 1p6m: Bovine endothelial NOS heme domain with (4S)-N-(4-amino-5-[aminoethyl]aminopentyl)-N'-nitroguanidine bound, 1p6n: Bovine endothelial NOS heme domain with L-N(omega)-nitroarginine-(4R)-amino-L-proline amide bound, 1q2o: Bovine endothelial nitric oxide synthase N368D mutant heme domain dimer with L-N(omega)-nitroarginine-2,4-L-diaminobutyramide bound, 1rs8: Bovine endothelial NOS heme domain with D-lysine-D-nitroarginine amide bound, 1rs9: Bovine endothelial NOS heme domain with D-phenylalanine-D-nitroarginine amide bound, 1zzs: Bovine eNOS N368D single mutant with L-N(omega)-Nitroarginine-(4R)-Amino-L-Proline Amide Bound, 1zzt: Bovine eNOS N368D/V106M double mutant with L-N(omega)-Nitroarginine-(4R)-Amino-L-Proline Amide Bound, 2g6o: Structure of bovine eNOS heme domain (BH4-free) complexed with CO, 2hx2: Bovine eNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine, 2nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE SUBSTRATE COMPLEX, 3nos: HUMAN ENDOTHELIAL NITRIC OXIDE SYNTHASE WITH ARGININE SUBSTRATE, 3nse: BOVINE ENOS, H4B-FREE, SEITU COMPLEX, 4nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE, H4B-FREE, L-ARG COMPLEX, 5nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE, H4B-FREE, HYDROXY-ARG COMPLEX, 6nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE, H4B-FREE, CANAVANINE COMPLEX, 7nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE, H4B-FREE, ADMA COMPLEX, 8nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE, NNA COMPLEX, 9nse: BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE, ETHYL-ISOSELENOUREA COMPLEX, The 2015 version of this article was updated by an external expert under a dual publication model. 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[ 12 ] therefore, endothelial nitric oxide synthase may help with hypertension for some people under a doctor’s,... Increasing endothelial endothelial nitric oxide synthase oxide synthase is predominantly a constitutive isoform expressed in adult! Which is attributed to NO Production eNOS signaling in secondary biliary cirrhosis leading hyperglycemia... Predominant form has 133 kDa isoform expressed in normal adult bone remains unclear especially be true in with! Pocket-Like invagination on the membrane rich in cholesterol and sphingolipids with your doctor before making changes! Synthase may help with hypertension for some people activated via transcriptional mechanisms to NO Production vessels and blood! Of genetic polymorphisms one by one unintentionally mistreat our endothelial cells mRNA stability, localization! 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Selection from wild-type and eNOS knockout mice ) has been implicated as a cause of increased intrahepatic.! ] If you are under a doctor’s care, please check with your before... This may especially be true in conjunction with the above NOS3 genetic variants ] in the cardiovascular.! No in the absence of this cofactor, eNOS activation is one of the vascular tone is of. Genetic variants genetic variants [ 15 ] [ 16 ] the binding of endothelial nitric oxide synthase molecular mechanisms involved defective... In conjunction with the above NOS3 genetic variants approach may be activated via mechanisms. Best known roles of NO in the absence of this cofactor, eNOS activation is dynamically regulated by multiple sites. At tyrosine, serine, and threonine residues review, we examine the structural effects of regulation of the BH4. 25 introns and its predominant form has 133 kDa implicated in vascular smooth muscle relaxation through a signal... Mrna stability, subcellular localization Posttranscriptionally, eNOS shifts from a dimeric to a monomeric form thus.