Endothelial Nitric Oxide Synthase Gene/Gender Interactions and the Renal Hemodynamic Response to Angiotensin II (original) (raw)
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American Journal of Hypertension - AMER J HYPERTENS, 2007
Background: Reduced synthesis of nitric oxide (NO) is considered a major proatherogenic mechanism in patients with end-stage renal disease (ESRD), but genetic factors impinging on this mechanism have been little studied in this population.Methods: We tested the relationship between carotid intima–media thickness (IMT) and three endothelial NO synthase (eNOS) polymorphisms (G894T, T-786C, and 27-bp repeat in intron 4) in an ethnically and geographically homogeneous group of 147 patients with ESRD.Results: The IMT was significantly thicker (P = .01) in patients with the TT genotype (G894T polymorphism) than in patients with TG or GG genotypes, and a similar association was observed for the T-786C polymorphism (P = .02). These relationships remained statistically significant (P = .02 and .01), also in multivariate models including traditional and emerging risk factors for atherosclerosis. Moreover, there was a direct association between the number of risk alleles and IMT (no risk allel...
Blood Coagulation & Fibrinolysis, 2011
To investigate the relationship between 27 bp repeat polymorphism in intron 4 in the endothelial nitric oxide synthase (eNOS4) gene and essential hypertension in the Kazakh Chinese population, 151 patients with essential hypertension and 138 healthy people were selected from the Boertonggu countryside of Shawan region in the Xinjiang Uygur Autonomous Region of China in 2006. The polymorphism of eNOS in the two groups was detected with polymerase chain reaction assays and the genotype frequencies in each group were calculated following the Hardy-Weinberg law. Four and five tandem 27 bp repeats were designated as "a" and "b", respectively. It was found that the frequencies of b/b, b/a and a/a genotypes of the eNOS4 gene were 84.06%, 15.22% and 0.72% in the control group, and 81.46%, 15.89% and 2.65% in the hypertension group, respectively. The frequencies of gene "b" and "a" were 91.67% and 8.33% in the control group and 89.40% and 10.60% in the hypertension group, respectively. It was found that plasma eNOS activity was not associated with genotypes and alleles of eNOS gene. Plasma eNOS activity in the hypertension group was significantly decreased compared with the control group (P<0.01). The results suggest that eNOS4 gene polymorphisms are unlikely to be the major genetic susceptibility factors for essential hypertension in the Xinjiang Kazakh population. However, a positive association between plasma eNOS activity and essential hypertension has been revealed. *C or r es pon di ng a u t ho r : Tel , 8 6 -2 8 -8 5 5 0 1 2 6 8 ; E-m a i l,
Balkan Medical Journal, 2016
Background: Chronic kidney diseases are known to influence nitric oxide metabolites (NOx) and asymmetric dimethylarginine (ADMA), though the exact mechanism is still poorly understood. Aims: The purpose of the present study was to examine eNOS Glu298Asp gene polymorphism, plasma NOx and ADMA concentration in subjects with and without End-stage Renal Disease. Study Design: Case-control study. Methods: In this study, genotype distributions of Glu-298Asp in exon 7 of the eNOS gene polymorphisms in 130 hemodialysis and 64 peritoneal dialysis patients were compared with 92 controls. NOx was measured by using the Griess reaction while arginine, ADMA and SDMA measurements were performed by HPLC. Genotyping for eNOS Glu298Asp polymorphism was detected with the polymerase chain reaction and/or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: When the genotype frequencies of TT and GT genes were compared between both groups, there was no detected statistically important difference, eventhough a TT genotype frequency was 27 (20.8%) versus 17 (26.6%), GT heterozygote genotype frequency was 52 (40%) versus 22 (34.4%), and GG homozygote genotype frequency was 51 (39.2%) versus 25 (39.1%), respectively (p>0.05). NOx, SDMA and ADMA concentrations were significantly elevated in subjects with hemodialysis patients as compared to their corresponding controls. Whereas nitrite was found to be significantly decreased in the patient with peritoneal dialysis. Conclusion: Not observed any connection between the Glu298Asp polymorphism in the eNOS gene and end-stage Renal Diseases in our study population under different dialysis treatments. However, higher ADMA and SDMA concentrations in subjects with ESRD support the existing hypothesis that NOx overproduction affects endothelial dysfunction. Thus, the reduction of ADMA and SDMA concentrations might play a protective role in ESRD patients.
Association between endothelial NO synthase polymorphism (rs3918226) and arterial properties
Artery Research, 2013
Background: Recently, rs3918226 polymorphism in the promoter region of endothelial NO synthase (eNOS) was strongly associated with arterial hypertension in a large genome-wide association study. We investigated whether this polymorphism was associated with arterial phenotypes in a Czech general population. Methods: In a pilot study, we genotyped 101 untreated subjects (mean age, 54.0 years). Arterial properties were measured using SphygmoCor. We used robust multivariate analysis to assess whether rs3918226 was associated with peripheral or central blood pressure, carotidfemoral pulse wave velocity (PWV) and aortic augmentation index (AIx). As independent covariates we considered sex, age, MAP, heart rate and smoking. Results: Frequencies of rs3918226 genotypes were CC 85.2%, CT 14.8%, and TT 0%. Current smokers carrying mutated T allele had marginally higher PWV (10.0 AE 0.8 vs. 8.7 AE 0.4 m/s; P Z 0.051) and significantly higher AIx (172.2 AE 6.8 vs. 153.2 AE 3.8%; P Z 0.024) compared to CC homozygotes. In non-smokers we did not find any association between rs3918226 and arterial properties (P ! 0.62). Moreover, we did not observe any association between either peripheral or central blood pressure and the polymorphism under study (P ! 0.58). Conclusions: This is the first study to explore the association of rs3918226 polymorphism in eNOS gene with arterial properties. Mutated T allele was associated with higher PWV and AIx in smokers. We hypothesize that genetic modulation of intermediate arterial phenotypes might lead to higher blood pressure. As the prevalence of T allele is low, further study with a sufficient number of subjects is warranted.
International Journal of Cardiology, 2007
Background: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) mediates a wide range of processes, and abnormal NO production mediated diabetes complications, including diabetic nephropathy (DN). In view of their impact on eNOS activity, polymorphisms in eNOS gene were described as candidates for atherosclerosis and DN. Aims: We evaluated the association of −786TNC (promoter region), Glu298Asp (Exon 7), and 4b4a (Intron 4) polymorphisms in eNOS gene with Type 2 diabetes mellitus (T2DM) and DN by haplotype analysis. Subjects and Methods: Study subjects comprised 515 DN patients, 402 normoalbuminuric [diabetes with no nephropathy (DWN)] T2DM patients, and 748 healthy subjects. −786TNC and Glu298Asp genotyping were done by PCR-RFLP analysis. Results: Higher prevalence of mutant Asp298, 4a, and −786C alleles and homozygous Asp298/Asp298 and 4a/4a genotypes were seen in T2DM patients compared to healthy subjects, with increased Asp298/Asp298 seen in DN compared to DWN patients (Pb.05). Three-loci haplotype analysis demonstrated significant association between eNOS variants and T2DM, with protective, neutral, T2DM, and DN-susceptible haplotypes identified, the latter including Asp298/4b/−786T and the Asp298/4a/−786C haplotypes that were present at higher frequencies among DN than among DWN patients. Multivariate regression analysis identified only Asp298/4a/−786T haplotype to be associated with DN (P=.047) after controlling for potential covariates. Conclusion: Genetic variation at the eNOS locus is associated with T2DM. It can serve as a useful genetic marker of increased susceptibility to T2DM and its complications, including the risk of nephropathy.
Association of eNOS Glu298Asp Polymorphism With End-Stage Renal Disease
Hypertension, 2002
Nitric oxide (NO) derived from endothelial cells is profoundly related to the maintenance of physiological vascular tone. Impairment of endothelial NO generation brought about by gene polymorphism is considered the major deterioration factor for progressive renal disease, including diabetic nephropathy. The present study aimed to elucidate the Glu298Asp polymorphism of endothelial NO synthase (eNOS) in patients with end-stage renal disease (ESRD) and its role as a predisposing factor for cardiovascular complications. Glu298Asp in exon 7 of the eNOS gene was determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis, in ESRD patients (nϭ185) and compared with that of unrelated healthy individuals (nϭ304). The occurrence of 298Asp was significantly higher in the ESRD group (Pϭ0.0020; odds ratio [OR] 1.65; 95% confidential interval [CI]: 1.21 to 2.25). In this group, 72 patients had type 2 diabetes mellitus (DM). Although 298Asp did not reach a significant level in the non-DM ESRD subgroup, the occurrence of 298Asp was significantly higher in DM-derived ESRD patients (Pϭ0.0010; OR 2.02; 95% CI: 1.37 to 3.07). The functional effect of the Glu298Asp was examined using Chinese hamster ovary (CHO) cells stably overexpressing either 1917G or 1917T. NO-selective electrode measurements and fluorometric nitrite assay revealed a statistically significant difference in NO production or nitrite accumulation between CHO 1917G and 1917T (PϽ0.01). These data indicated that Glu298Asp is the predisposing factor in ESRD, especially DM-derived ESRD. The functional difference in NO generation depending on eNOS with either glutamate or aspartate at position 298 was also confirmed in vitro. (Hypertension. 2002;40:535-540.)
Modifier effect of ENOS in autosomal dominant polycystic kidney disease
Human Molecular Genetics, 2002
A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with altered endothelial-dependent vasodilation and decreased vascular production of nitric oxide (NO). Thus, ENOS, the gene coding for the endothelial nitric oxide synthase (eNOS), could have a modifier effect in ADPKD. In order to test this hypothesis, we genotyped 173 unrelated ADPKD patients from Belgium and the north of France for the Glu298Asp, intron 4 VNTR and T-786C polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In males (n = 93), the Glu298Asp polymorphism was associated with a lower age at ESRD (Glu/Asp + Asp/Asp: 49.0 ± 1.2 years, n = 53; Glu/Glu: 53.5 ± 1.5 years, n = 40; simple regression, P = 0.02; multiple regression, P = 0.006). This effect was confirmed in a subset of males linked to PKD1 and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NO synthase (NOS) activity was decreased in renal artery samples from ADPKD males harbouring the Asp298 allele, in association with posttranslational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. In conclusion, the frequent Glu298Asp polymorphism of ENOS is associated with a 5 year lower mean age at ESRD in this subset of ADPKD males. This effect could be due to a decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO.
European review for medical and pharmacological sciences, 2014
INTRODUCTION Endothelial dysfunction is recognized as an early and initiating event in the pathogenesis of coronary artery disease. Gene polymorphisms of endothelial constitutive nitric oxide synthase (ecNOS), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) have been found to be associated with atherosclerosis. We aimed to investigate the possible effects of ecNOS, ACE and AT1R gene polymorphisms on endothelial functions in healthy population. MATERIALS AND METHODS In 255 healthy subjects (male/female: 119/136 mean age 35.1±2.3 years) ecNOS, ACE and AT1R gene polymorphisms were assessed by polymerase chain reaction (PCR). Endothelium dependent (EDD, flow-mediated) and endothelium independent vasodilation (EID) were measured by high resolution brachial artery ultrasound and 0.5 mg sublingual nitroglycerine respectively. RESULTS ecNOS and ACE genes had no significant effect on EDD and EID. However, subjects with AT1RAC+CC genotypes had lower EDD compare...