Cloning and structural characterization of the human endothelial nitric‐oxide‐synthase gene

Miyahara, Katsunori; Kawamoto, Takeshi; Sase, Kazuhiro; Yui, Yoshiki; Toda, Katsumi; Yang, Lixia; Hattori, Ryuichi; Aoyama, Takeshi; Yamamoto, Yasutake; Doi, Yoshinori; Ogoshi, Shohei; Hashimoto, Kozo; Kawai, Chuichi; Sasayama, Shígetake; Shizuta, Yutaka

doi:10.1111/j.1432-1033.1994.tb19045.x

Cited by 150 publications

(74 citation statements)

References 49 publications

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“…43,44 Analysis of the eNOS promoter sequence did not reveal the presence of any discernible PPAR response elements. Because neither 15d-PGJ 2 nor ciglitazone treatment increased eNOS mRNA or protein levels, it seems likely that PPAR␥ ligands regulate the expression of another target gene that promotes increased EC ·NO release, particularly because 15d-PGJ 2 increased ·NO release but decreased eNOS protein expression.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Calnek

Mazzella

Roser

et al. 2003

ATVB

276

158

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Objective-Peroxisome proliferator-activated receptor ␥ (PPAR␥) ligands reduce lesion formation in animal models of atherosclerosis by mechanisms that have not been defined completely. We hypothesized that PPAR␥ ligands stimulate endothelial-derived nitric oxide release (·NO) to protect the vascular wall. Methods and Results-The PPAR␥ ligands, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) or ciglitazone, stimulated a PPAR response element-luciferase reporter construct in transfected porcine pulmonary artery endothelial cells (PAECs), demonstrating that PPAR␥ was transcriptionally functional. Treatment with 15d-PGJ 2 or ciglitazone significantly increased release of ·NO from PAECs or human aortic endothelial cells and augmented calcium ionophore-induced ·NO release from human umbilical vein endothelial cells measured by chemiluminescence analysis of culture media. Increases in ·NO release caused by treatment with 15d-PGJ 2 occurred at 24 hours, but not after 1 to 16 hours, and were abrogated by treatment with the transcriptional inhibitor ␣-amanitin. Overexpression of PPAR␥ or treatment with 9-cis retinoic acid also enhanced PAEC ·NO release. Neither 15d-PGJ 2 nor ciglitazone altered eNOS mRNA, whereas 15d-PGJ 2 , but not ciglitazone, decreased eNOS protein. Key Words: peroxisome proliferator-activated receptor ␥ Ⅲ endothelium Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ thiazolidinedione T he production of nitric oxide (·NO) by vascular endothelial cells is critical for maintenance of normal vascular physiology. 1 In endothelial cells (ECs), the type III endothelial nitric oxide synthase (eNOS) produces ·NO from the amino acid L-arginine. Our preliminary observations, 2 as well as reports by others, [3][4][5] indicate that exogenous fatty acids alter EC ·NO production. The molecular mechanism contributing to fatty acid-induced alterations in EC ·NO production remain unexplored. One potential mechanism for fatty acidinduced alterations in gene expression is the activation of peroxisome proliferator-activated receptors (PPARs). Originally described in 1990, PPARs belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors including steroid, thyroid, and retinoid hormone receptors. 6 Structurally diverse ligands including long-chain fatty acids, eicosanoids, thiazolidinediones, and fibrates activate PPARs, which form obligate heterodimers with the 9-cis retinoic acid receptor, RXR. 7 On ligand binding, PPARs become transcriptionally active at PPAR response elements (PPRE) and alter the expression of target genes. Conclusions-TakenPPAR␥ is expressed in vascular endothelial cells 8 -11 and smooth muscle cells. 12 The expression of PPARs in vascular wall cells suggests their potential role in vascular disease. 8 -10 Some in vitro studies suggest potential atherogenic effects of PPAR␥ activation, 8,[13][14][15] whereas other studies associate PPAR␥ with potential vascular protective effects. 16 -21 Importantly, two independent in vivo studies using the LDL receptor knockout mouse demo...

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Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Calnek

Mazzella

Roser

et al. 2003

ATVB

276

158

View full text Add to dashboard Cite

show abstract

“…16 The consensus sequence GAAGTCTA GACCTGCTGCA/GGGGGTGAG in which the first three repeats have A and last two repeats have G at the 19th base has been defined. 17 A new polymorphism consisting of an additional 27 bp repeat (4C) was found at very low frequency in a Caucasian population without significant association with coronary artery disease or hypertension. 18 Although the precise molecular effects of these polymorphisms have not been elucidated, there is biochemical evidence of reduced eNOS protein expression and enzymatic activity associated with eNOS intron 4 VNTR and TÀ786C polymorphism variants.…”

Section: Introductionmentioning

confidence: 99%

Association analysis of endothelial nitric oxide synthase gene polymorphism with primary hypertension in a Singapore population

et al. 2006

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Vascular endothelial cells produce nitric oxide (NO), which contributes to the regulation of blood pressure and regional blood flow. Endothelial nitric oxide synthase (eNOS) gene polymorphisms are associated with coronary artery disease, but their linkage with primary hypertension is controversial. A total of 103 individuals with primary hypertension and 104 normotensive control subjects were studied in Singapore. The specific genotypes for G894T missense variant in exon 7, variable number tandem repeats (VNTR) in intron 4 (eNOS 4A/B/C) and TÀ786C in the promoter were isolated using allele-specific gene amplification and restriction fragment length polymorphism to examine the association of genotype and allelic frequency in both groups. Logistic regression analysis was also used to detect the association between genotypes and hypertension. Five genotypes of intron 4 VNTR (AA, AB, BB, AC and BC) were observed. Intron 4 B/B genotype was significantly associated with the hypertension group (P ¼ 0.035), but disequilibrium of G894T and TÀ786C was absent between the two groups (P ¼ 0.419 and P ¼ 0.227), respectively. The overall distribution of allelic frequency differed significantly between the two groups, with four-repeat allele (4A) of intron 4 more frequent in the normotensive group than the hypertensive group (P ¼ 0.019). Logistic regression analysis showed that intron 4 B/B genotype was significantly associated with systolic blood pressure of individuals with body mass index greater than 25 kg/m 2 (P ¼ 0.04). In conclusion, the eNOS 4 B/B genotype is a genetic susceptibility factor for primary hypertension in a Singapore population.

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“…The eNOS gene is located on chromosome 7q35-36 and consists of 26 exons (Miyahara et al, 1994). Several polymorphisms have been identified and much attention has been focused on the following variants: G894T, 4b/a, T-786C, and A922G (Thomas et al, 2001;Thaha et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Endothelial nitric oxide synthase gene polymorphisms and essential hypertension in Han Chinese

Wang¹,

Wang²,

Chang³

et al. 2010

Genet. Mol. Res.

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ABSTRACT.We examined the effect of polymorphisms in the endothelial nitric oxide synthase gene on the risk for essential hypertension in a Han Chinese population through a meta-analysis of data from 15 studies. Associations between increased risk for essential hypertension and 4b/a were obtained in a dominant model and allele contrast (aa + ab vs bb: odds ratio (OR) FE = 1.26, 95% confidence interval (CI) = 1.10-1.44; a vs b allele: OR FE = 1.23, 95%CI: 1.09-1.40). Four studies with sample sizes over 500 produced similar results. No evidence of publication bias was found. Also, no significant heterogeneity was observed among these studies. When we examined 1897 ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 9 (3): 1896-1907 (2010) eNOS polymorphisms and essential hypertension in Han Chinese the G894T polymorphism, we found a marginally significant association for allele contrast and the recessive model when all the eligible studies were pooled together. However, there was no evidence for a significant association after the exclusion of two studies deviating from HardyWeinberg equilibrium in the control group. Heterogeneity among studies was observed. Results of cumulative and recursive cumulative meta-analysis indicated that more studies are needed to objectively determine the effects of these two polymorphisms.

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Cloning and structural characterization of the human endothelial nitric‐oxide‐synthase gene

Cited by 150 publications

References 49 publications

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Peroxisome Proliferator-Activated Receptor γ Ligands Increase Release of Nitric Oxide From Endothelial Cells

Association analysis of endothelial nitric oxide synthase gene polymorphism with primary hypertension in a Singapore population

Endothelial nitric oxide synthase gene polymorphisms and essential hypertension in Han Chinese

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