Disease relevance of NOS3

• Furthermore, we show that NOS3 promotes thrombosis in vivo [1].
• Polymorphisms of NOS3, the gene that codes for endothelial nitric oxide synthase, have been associated with essential hypertension [2].
• CONCLUSIONS: This study provides evidence of an association between the NOS3 gene and subjects with glaucoma who have a history of migraine [3].
• We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low [4].
• Sepsis is associated with reciprocal expressional modifications of constitutive nitric oxide synthase (NOS) in human skeletal muscle: down-regulation of NOS1 and up-regulation of NOS3 [5].
• The relation between several NOS3 polymorphisms and the high tension variant of primary open-angle glaucoma is modified by postmenopausal hormone use. [6]

Psychiatry related information on NOS3

• The distribution of the Glu298Asp polymorphism in NOS3 gene was determined in 405 Italian patients with "probable" Alzheimer's disease (AD) compared with 253 age-matched controls [7].
• Recently, polymorphisms in the endothelial constitutive nitric oxide synthase 3 (NOS3) and also the inducible nitric oxide synthase gene (NOS2A) have been suggested to lead to increased risk of Alzheimer's disease (AD) or dementia with Lewy bodies [8].
• The present study examines the existence and location of the constitutive isoform eNOS (endothelial NO synthase) accompanying the already substantiated neurogenic NOS (nNOS) in the human corpus cavernosum of men with and without erectile dysfunction [9].
• NOS3 G894T genotype was not significantly associated, either independently or interactively with habitual physical activity (PA) level, with SBP, Q, TPR, or a-vO2 diff during submaximal or maximal exercise [10].
• We compared eNOS expression in gentamicin-treated and non-treated guinea pigs in the second turn of the cochlea, an area corresponding to speech perception in humans [11].

High impact information on NOS3

• The recent colocalization of the cationic amino acid transporter CAT-1 (system y(+)), nitric oxide synthase (eNOS), and caveolin-1 in endothelial plasmalemmal caveolae provides a novel mechanism for the regulation of NO production by L-arginine delivery and circulating hormones such insulin and 17beta-estradiol [12].
• These data refute the idea that NOS3 is obligatory for the normal autonomic control of cardiac muscle function [13].
• Here we demonstrate that the serine/threonine protein kinase Akt/PKB mediates the activation of eNOS, leading to increased NO production [14].
• Inhibition of the phosphatidylinositol-3-OH kinase/Akt pathway or mutation of the Akt site on eNOS protein (at serine 1177) attenuates the serine phosphorylation and prevents the activation of eNOS [14].
• Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is a fundamental determinant of cardiovascular homesotasis: it regulates systemic blood pressure, vascular remodelling and angiogenesis [14].

Chemical compound and disease context of NOS3

• Tyrosine phosphorylation of NOS3 in a breast cancer cell line and Src-transformed cells [15].
• In this study, wild-type and mutant forms of eNOS have been expressed in a baculovirus system, and the quaternary structure of the purified enzymes has been analyzed by low temperature SDS-PAGE. eNOS dimer formation requires incorporation of the heme prosthetic group but does not require myristoylation or CaM or BH4 binding [16].
• Inhibition of phosphatidylinositol 3-kinase and ERK1/2 inhibited eNOS activity, whereas pertussis toxin and the ER antagonists ICI 182,750 and tamoxifen had negligible effects [17].
• Forskolin and methotrexate, which induce biochemical differentiation/ growth arrest in choriocarcinoma cells, stimulate eNOS mRNA and protein synthesis, but cannot overcome the decline of eNOS polypeptide levels during hypoxic incubation [18].
• Increased eNOS and iNOS expression in adipocytes and local effects of insulin and Ang II may increase adipose tissue production of NO in obesity [19].

Biological context of NOS3

• RESULTS: In contrast to cells of other genotypes, endothelial cells of the (-786)C/C genotype did not reveal an increase in NOS3 expression upon exposure to IL-10, and the cytokine failed to suppress IL-12 expression upon stimulation of CD40 [20].
• This may be explained by the IL-10 insensitivity of the C-type NOS3 gene promoter and the resulting failure to subdue CD40-mediated proinflammatory gene expression [20].
• Interestingly, a promoter variant of the NOS3 gene, the (-786)C variant, is insensitive to shear stress, and individuals homozygous for this single-nucleotide polymorphism (SNP) have an increased risk of developing coronary artery disease [20].
• These results pave the way for studies looking for the influence of NOS3 on blood pressure in high-risk subsets such as diabetic or hypertensive patients [2].
• CONCLUSION: We show for the first time a highly significant association of ambulatory blood pressure with NOS3 haplotypes in well-characterized white individuals from Flanders [2].

Anatomical context of NOS3

• NOS III (NOS3, ecNOS) is expressed mainly in endothelial cells [21].
• The human alveolar type II epithelium-like cell line A549 expresses nitric oxide synthase type 2 (NOS2), but not NOS3, and produces nitric oxide (NO) upon appropriate stimulation [22].
• OBJECTIVE: To study the expression (mRNA and protein) and activity of the constitutive isoforms of nitric oxide synthase (NOS1 and NOS3) in a skeletal muscle of septic patients [5].
• However, relatively little is known regarding the NOS2 and NOS3 expression of type II human alveolar epithelial cells (AEC II) in primary culture [22].
• Consistent with the targeting of overexpressed NOS3 to caveolae in the vicinity of cholinergic and adrenergic receptors, these studies have highlighted the importance of NOS3-derived NO in the modulation of autonomic cardiac stimulation [23].

Associations of NOS3 with chemical compounds

• Influence of the Glu298Asp polymorphism of NOS3 on age at onset and homocysteine levels in AD patients [7].
• NOS3 protein expression was verified by Western blot, and measuring nitrate/nitrite revealed that the protein is active [22].
• The frequencies of the NOS3 Glu298Asp genotypes were Glu/Glu=46.2%, Glu/Asp=42.7%, and Asp/Asp=11.1% [24].
• PWV did not differ by MTHFR C677T or NOS3 G894T genotype, even when smoking and folate sub-groups were considered [25].
• We investigated the tyrosine phosphorylation of NOS3 by active Src [15].

Physical interactions of NOS3

• Loss of the DNA binding domain did not change E2 activation of Src or erk, but ligand-induced PI3 kinase-ERalpha binding and eNOS phosphorylation did not occur [26].
• We identified four consensus sequences for Stat3 binding (SIE) in the eNOS promoter at positions -1520, -1024, -840, and -540 [27].
• BACKGROUND: Estrogens can upregulate endothelial nitric oxide synthase (eNOS) in human endothelial cells by increasing eNOS promoter activity and enhancing the binding activity of the transcription factor Sp1 [28].
• In this study, we examined whether the modulation of the stoichiometry of the caveolin/eNOS complex in EC lining tumor blood vessels could affect the tumor vasculature and consecutively tumor growth [29].
• Regulation of the endothelial isoform of nitric oxide synthase (eNOS) appears to be much more complex in comparison to that of other NOS isoforms [30].

Enzymatic interactions of NOS3

• As expected there was only a weak colocalization between eNOS phosphorylated at Ser-1177 and caveolin-1 [31].
• Besides acting as an allosteric enhancer, Hsp90 was shown to serve as a module recruiting Akt to phosphorylate the serine 1179/1177 (bovine/human) residue of eNOS [32].
• AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and activate eNOS at Ser-1177 in vitro, yet the function of AMPK in endothelium is poorly characterized [33].
• Despite the narrowing of arterial diameter and reduced expression of eNOS, expressions of phosphorylated protein kinase B (Akt) and phosphorylated eNOS were significantly increased in spastic arteries [34].

Co-localisations of NOS3

• Endothelial NOS protein co-localized to areas that showed positive NADPH diaphorase activity [35].
• However, within 10 min following addition of TRAIL, nearly all the cells showed an increased cytoplasm localization of eNOS which appeared co-localized with the Golgi apparatus at a higher extent than in unstimulated cells [36].
• NOSTRIN colocalized extensively with eNOS at the plasma membrane of confluent human umbilical venous endothelial cells and in punctate cytosolic structures of CHO-eNOS cells [37].
• Stimulatory phosphorylation of eNOS (Ser1177) was also reduced in moderately hyperglycemic diabetic rats. eNOS colocalized and interacted with CAV-1 in endothelial cells throughout the renal vascular tree both in control and moderately hyperglycemic diabetic rats [38].

Regulatory relationships of NOS3

• In reconstituted, estrogen-stimulated COS-7 (ER-null) cells, membrane ER46 more efficiently triggered membrane eNOS phosphorylation than ER66 [39].
• NO production was significantly reduced in eNOS-expressing CHO cells (CHO-eNOS) that transiently overexpressed NOSIP [40].
• Nitric-oxide synthase (NOS) reductase domain models suggest a new control element in endothelial NOS that attenuates calmodulin-dependent activity [41].
• The endothelial NOS gene transfer also inhibited thymidine incorporation into type A receptor-transfected cells in response to endothelin-1, which was abolished in the presence of the NOS inhibitor N(G)-monomethyl-L-arginine acetate [42].
• Moreover, the protein level of eNOS is upregulated in response to VEGF-A [43].

Other interactions of NOS3

• Thus, eNOS and iNOS proteins are differentially expressed in healthy human liver, and this expression is significantly altered in cirrhotic liver disorders [44].
• ER46 more efficiently modulates membrane-initiated estrogen actions, including eNOS activation, than full-length ER66 [39].
• Here we identify the 110-kDa caveolin-binding protein striatin as the molecular anchor that localizes ERalpha to the membrane and organizes the ERalpha-eNOS membrane signaling complex [45].
• Both growth factor-independent (HMC-1) and -dependent (LAD 2) MC lines showed predominant nuclear eNOS protein localization, with weaker cytoplasmic expression. nNOS showed exclusive cytoplasmic localization in HMC-1 [46].
• Taxotere prevented the VEGF-induced phosphorylation of focal adhesion kinase, Akt, and endothelial nitric oxide synthase (eNOS), all of which are Hsp90 client proteins [47].

Analytical, diagnostic and therapeutic context of NOS3

• METHODS: Endothelial cells were isolated from human umbilical cord veins, clonally expanded, and analyzed for NOS3 and IL-12 expression by real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay [20].
• METHODS: We used the linear variable transducer technique to compare dorsal hand vein compliance in 31 young, healthy men ( GNB3 C825T: 15 CC, 14 CT, and 2 TT; NOS3 T-786C: 14 TT, 13 TC, and 4 CC) [48].
• In situ hybridization confirmed that AEC II express NOS3, but not NOS2 mRNA in vivo [22].
• RESULTS: Immunohistochemistry disclosed NOS2 and NOS3 immunoreactivity in PTC cells, the percentage of positive cells being greater than normal (P < 0.02) [49].
• Real-time quantitative polymerase chain reaction (RTQ-PCR) showed that NOS2 and NOS3 mRNA levels were, respectively, increased (P < 0.02) by 2.6 +/- 0.6 and 4.2 +/- 1.1 times in PTC [49].

References