Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity

Wang, Xing Li; Sim, Ah Siew; Wang, Min Xia; Murrell, George A. C.; Trudinger, Brian J.; Wang, Jian

doi:10.1016/s0014-5793(00)01356-9

Cited by 211 publications

(161 citation statements)

References 25 publications

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“…It was reported that smoking decreases activity of eNOS and may modify the relationship between polymorphisms and expression levels. 20,21 For that reason, we performed multiple binary regression analysis (Table 4). Although smoking was a more powerful risk factor than 27-bp repeat polymorphism in total FHON patients, 4a allele was the only variable with statistical significance after adjustment of the effect of smoking in idiopathic group (p c ¼ 0.026, OR 4.302, 95% CI 1.359-13.621).…”

Section: Resultsmentioning

confidence: 99%

Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis

Koo

Lee

et al. 2006

Journal Orthopaedic Research

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As endothelial nitric oxide synthase (eNOS) has beneficial effects on skeletal, vascular, and thrombotic systems, the association between nontraumatic femoral head osteonecrosis (FHON) and eNOS gene polymorphisms was investigated in Korean patients with FHON. Genomic DNA from 103 patients with nontraumatic FHON (idiopathic in 50, steroid-induced in 29, and alcohol abuse in 24) and 103 control subjects matched for gender and age (3-year range) was analyzed for the 27-bp repeat polymorphism in intron 4 and Glu298Asp polymorphism in exon 7. The frequencies of alleles and genotypes were compared between patients and control subjects. The frequency of 4a allele was significantly higher in total patients than control subjects [6.8% vs. 2.4%, p ¼ 0.0345, odds ratio (OR) 2.931]. In subgroup analysis, the 4a allele significantly increased in patients with idiopathic FHON versus control subjects (9.0% vs. 2.4%, p ¼ 0.0297, OR 3.976). The frequency of the 4a/b genotype in total patients (13.6% vs. 4.9%, p ¼ 0.0302, OR 3.083) as well as patients with idiopathic FHON (18.0% vs. 4.9%, p ¼ 0.0246, OR 4.302) was higher than control subjects. The distribution of Glu298Asp polymorphisms was not significantly different between patients and control subjects. Microstellate polymorphism in intron 4 of eNOS polymorphism was significantly associated with idiopathic FHON in Korean patients. Because 4a allele is associated with lower synthesis of eNOS, these results suggest that carrier state of 4a allele in intron 4 might be a genetic risk factor of FHON and could provide insight into the protective role of nitric oxide in the pathogenesis of FHON. ß

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Section: Resultsmentioning

confidence: 99%

Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis

Koo

Lee

et al. 2006

Journal Orthopaedic Research

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“…The mechanisms of these two polymorphisms affecting eNOS activity are different. Glu298Asp polymorphism induces the structural change of the eNOS protein and reduces eNOS activity [10,11]. In contrast, a different study showed that in -786T-C mutation, replication protein A1 which is known as a DNA binding protein essential for DNA repair and replication, binds only to the mutant allele and reduces the promoter activity of the eNOS gene [12,28].…”

Section: Discussionmentioning

confidence: 97%

“…Two major polymorphisms have been found in the human eNOS gene: Glu298Asp (G894T) in exon 7 and -786T-C mutation in the 5′-flanking region. Glu298Asp causes a structural change of the eNOS Endothelial derived nitric oxide (NO), synthesized from L-arginine by the endothelium isoform of NO synthase (eNOS), mediates local vasodilation and plays protein and reduces eNOS activity [10,11]. In contrast, the -786T-C mutation reduces the promoter activity [12] and thus reduces eNOS protein expression and eNOS activity [10].…”

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confidence: 99%

“…Glu298Asp causes a structural change of the eNOS Endothelial derived nitric oxide (NO), synthesized from L-arginine by the endothelium isoform of NO synthase (eNOS), mediates local vasodilation and plays protein and reduces eNOS activity [10,11]. In contrast, the -786T-C mutation reduces the promoter activity [12] and thus reduces eNOS protein expression and eNOS activity [10]. Both Glu298Asp and -786T-C polymorphism have been reported to lead to abnormal vasomotility [13,14] and to be associated with vasoconstrictive angina [12,15].…”

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confidence: 99%

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Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

et al. 2002

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Aims/hypothesis. Endothelial derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with abnormal vasomotility and impaired local blood flow. A decrease in local blood flow has been reported to cause insulin resistance. The aim of this study was to examine a possible association of two eNOS polymorphisms, Glu298Asp (G894T) in exon 7 and -786T-C mutation with insulin resistance. Methods. Genotypes of both Glu298Asp and -786T-C mutation were examined by the PCR-RFLP method. Plasma nitrate and nitrite concentrations were also measured. Results. The allele frequencies of both polymorphisms showed no considerable differences in 233 non-diabetic subjects and 301 patients with Type II (non-insulin-dependent) diabetes mellitus. Non-diabetic subjects with the -786C allele had (p<0.05) higher fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the -786T/ -786T genotype. Diabetic subjects with -786C allele showed higher HbA 1c than those with the -786T/ -786T genotype. A euglycaemic hyperinsulinemic clamp study done on 71 of the 301 patients showed a lower glucose infusion rate in diabetic patients with the -786C allele than those without it. In diabetic patients with the -786C allele, plasma nitrate and nitrite concentrations were lower than in subjects without it (p=0.026). No differences were observed between mutant carriers of Glu298Asp and non-carriers among both nondiabetic subjects and Type II diabetic patients. Conclusions/interpretation. The -786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients. [Diabetologia (2002[Diabetologia ( ) 45:1594[Diabetologia ( -1601 Keywords Endothelial nitric oxide synthase, polymorphism, glucose infusion rate, homeostasis model assessment of insulin resistance insulin resistance, intima-media thickness. Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita City, Japan a key role in the regulation of vascular tone. Skeletal muscle glucose uptake is enhanced by insulin-mediated vasodilation and the decrease in local blood flow can result in insulin resistance [1][2][3][4][5]. However, several reports deny a major role of endothelial NO production in determining insulin sensitivity [6,7].Recently eNOS knockout mice have been reported to be insulin resistant [8]. These mice have also shown a decrease in whole-body and muscle-glucose uptake as well as the simultaneous decrease in the local blood flow [9]. Two major polymorphisms have been found in the human eNOS gene: Glu298Asp (G894T) in exon 7 and -786T-C mutation in the 5′-flanking region. Glu298Asp causes a structural change of the eNOS Endothelial derived nitric oxide (NO), synthesized from L-arginine by the endothelium isoform of NO synthase (eNOS), mediates local vasodilation and plays

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“…One recent example of the latter was noted in studies on the vascular endothelial nitric oxide (NO) synthase (eNOS) system. Changes in tissue NO levels occur in patients with chronic hypertension, atherosclerosis, and thrombotic disorders, and polymorphic forms of eNOS have been described [56], as have mutations in the promoter sequence for this gene [57]. One variant, the eNOS 4/4 allele, appears particularly sensitive to an environmental influence (cigarette smoke), and inducible changes in eNOS gene expression may be a useful model for the study of external influences on triggering SCD in high-risk genotypes.…”

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confidence: 99%

Genomics, heart failure and sudden cardiac death

Darbar

2008

Heart Fail Rev

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Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lowerrisk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD. KeywordsSudden cardiac death; Genomics; Heart failure; Single nucleotide polymorphisms Heart failure and SCD Heart failure (HF) afflicts approximately 5 million people in the United States, with 550,000 new cases reported annually, but as the population ages both the incidence and prevalence is expected to rise [1]. HF is associated with high mortality and is reportedly responsible for 300,000 deaths annually in the US [1]. Prior to advent of neuro-hormonal antagonists, the mean duration of survival after onset of HF was 1.7 years for men and 3.2 years for women, with only half of patients still alive after 5 years of onset [2]. The two modes of death in patients with HF are circulatory failure due to progressive left ventricular (LV) dysfunction associated with gradual worsening of symptoms, or sudden cardiac death (SCD) in relatively clinically stable patients [3].Although the proportion of sudden deaths in published trials varies significantly, probably due to varying interpretations of reported modes of death, clinical trials data suggests that SCD accounts for approximately one-third of all HF deaths [4]. Epidemiologic evidence from the Framingham heart study suggests that about one-half of all deaths due to HF occur...

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Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity

Cited by 211 publications

References 25 publications

Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis

Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis

Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

Genomics, heart failure and sudden cardiac death

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