Endothelial NOS

Last updated
NOS3
PDB 1m9j EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NOS3 , ECNOS, eNOS, nitric oxide synthase 3
External IDs OMIM: 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 Mb Chr 5: 24.57 – 24.59 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

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. [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

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

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

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

Related Research Articles

<span class="mw-page-title-main">Endothelium</span> Layer of cells that lining inner surface of blood vessels

The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

<span class="mw-page-title-main">Endothelium-derived relaxing factor</span> Nitric Oxide as an EDRF

The Endothelium-derived relaxing factor (EDRF) is a strong vasodilator produced by cardiac endothelial cells in response to stress signals such as high levels of ADP accumulation or hypoxia. Robert F. Furchgott is widely recognised for this discovery, even going so far as to be a co-recipient of the 1998 Nobel Prize in Medicine with his colleagues Louis J. Ignarro and Ferid Murad. Nitric oxide (NO) is a key component in any EDRF as these compounds either include NO or are structurally in the form of NO.

<span class="mw-page-title-main">Endothelial dysfunction</span>

In vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium. Along with acting as a semi-permeable membrane, the endothelium is responsible for maintaining vascular tone and regulating oxidative stress by releasing mediators, such as nitric oxide, prostacyclin and endothelin, and controlling local angiotensin-II activity.

<span class="mw-page-title-main">Nitric oxide synthase</span> Enzyme catalysing the formation of the gasotransmitter NO(nitric oxide)

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

<span class="mw-page-title-main">Tetrahydrobiopterin</span> Chemical compound

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (quinonoid dihydrobiopterin).

<span class="mw-page-title-main">Endothelin</span>

Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.

In blood vessels Endothelium-Derived Hyperpolarizing Factor or EDHF is proposed to be a substance and/or electrical signal that is generated or synthesized in and released from the endothelium; its action is to hyperpolarize vascular smooth muscle cells, causing these cells to relax, thus allowing the blood vessel to expand in diameter.

Gasotransmitters is a class of neurotransmitters. The molecules are distinguished from other bioactive endogenous gaseous signaling molecules based on a need to meet distinct characterization criteria. Currently, only nitric oxide, carbon monoxide, and hydrogen sulfide are accepted as gasotransmitters. According to in vitro models, gasotransmitters, like other gaseous signaling molecules, may bind to gasoreceptors and trigger signaling in the cells.

<span class="mw-page-title-main">Louis Ignarro</span> American pharmacologist

Louis Joseph Ignarro is an American pharmacologist. For demonstrating the signaling properties of nitric oxide, he was co-recipient of the 1998 Nobel Prize in Physiology or Medicine with Robert F. Furchgott and Ferid Murad.

<span class="mw-page-title-main">Caveolin 1</span> Protein-coding gene in the species Homo sapiens

Caveolin-1 is a protein that in humans is encoded by the CAV1 gene.

<span class="mw-page-title-main">GPX1</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3. This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans.

<span class="mw-page-title-main">NOS1</span> Protein-coding gene in the species Homo sapiens

Nitric oxide synthase 1 (neuronal), also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene.

<span class="mw-page-title-main">Dimethylargininase</span> Class of enzymes

In the field of enzymology, a dimethylargininase, also known as a dimethylarginine dimethylaminohydrolase (DDAH), is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">GUCY1B3</span> Protein-coding gene in the species Homo sapiens

Guanylate cyclase soluble subunit beta-1 is an enzyme that in humans is encoded by the GUCY1B3 gene.

Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension. It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.

Biological functions of nitric oxide are roles that nitric oxide plays within biology.

<span class="mw-page-title-main">Methylarginine</span> Chemical compound

N-Methylarginine is an inhibitor of nitric oxide synthase. Chemically, it is a methyl derivative of the amino acid arginine. It is used as a biochemical tool in the study of physiological role of nitric oxide.

<span class="mw-page-title-main">Pathophysiology of hypertension</span>

Pathophysiology is a study which explains the function of the body as it relates to diseases and conditions. The pathophysiology of hypertension is an area which attempts to explain mechanistically the causes of hypertension, which is a chronic disease characterized by elevation of blood pressure. Hypertension can be classified by cause as either essential or secondary. About 90–95% of hypertension is essential hypertension. Some authorities define essential hypertension as that which has no known explanation, while others define its cause as being due to overconsumption of sodium and underconsumption of potassium. Secondary hypertension indicates that the hypertension is a result of a specific underlying condition with a well-known mechanism, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or endocrine disorders such as excess aldosterone, cortisol, or catecholamines. Persistent hypertension is a major risk factor for hypertensive heart disease, coronary artery disease, stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease.

<span class="mw-page-title-main">Protein detoxification</span>

Protein detoxification is the process by which proteins containing methylated arginine are broken down and removed from the body.

<span class="mw-page-title-main">20-Hydroxyeicosatetraenoic acid</span> Chemical compound

20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regulation of vascular tone, blood flow to specific organs, sodium and fluid transport in the kidney, and vascular pathway remodeling. These vascular and kidney effects of 20-HETE have been shown to be responsible for regulating blood pressure and blood flow to specific organs in rodents; genetic and preclinical studies suggest that 20-HETE may similarly regulate blood pressure and contribute to the development of stroke and heart attacks. Additionally the loss of its production appears to be one cause of the human neurological disease, Hereditary spastic paraplegia. Preclinical studies also suggest that the overproduction of 20-HETE may contribute to the progression of certain human cancers, particularly those of the breast.

References

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