Modulation of nitric oxide formation by endothelial nitric oxide synthase gene haplotypes

Metzger, Ingrid F.; Sertório, Jonas T.; Tanus‐Santos, José Eduardo

doi:10.1016/j.freeradbiomed.2007.06.012

Cited by 97 publications

(63 citation statements)

References 41 publications

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“…NO is a major player in the regulation of vascular tone and in protecting target organs, 9,22 and altered NO availability has been associated with eNOS genetic variations [23][24][25] and with hypertensive disorders of pregnancy. 16,26 Although no earlier study has examined whether eNOS polymorphisms or haplotypes modify the effects of drugs used to treat GH or PE, a few studies showed that eNOS polymorphisms affect the responses to drugs that upregulate eNOS expression or increased NO release.…”

Section: Discussionmentioning

confidence: 99%

eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension

et al. 2009

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Variations of the endothelial nitric oxide synthase (eNOS) gene have been associated with hypertensive disorders of pregnancy. We examined whether eNOS polymorphisms affect the therapeutic responses of women with gestational hypertension (GH) or preeclampsia (PE). We studied 304 hypertensive pregnant women (152 GH and 152 PE), who were stratified according to clinical and laboratorial parameters of therapeutic responsiveness. We compared the frequencies of three eNOS genetic polymorphisms (T-786C, Glu298Asp and b/a intron 4) in responsive and nonresponsive PE and GH patients. We found no significant differences in genotype or allele distributions when responsive and nonresponsive groups were compared (both PE or GH; all P40.05). However, the eNOS haplotype distribution differed in PE (but not in GH)-responsive and -nonresponsive groups (P ¼ 0.0003). The 'C-Glu-a' and 'T-Asp-a' hapotypes were associated with responsiveness and nonresponsiveness to therapy, respectively (both Po0.001), thus suggesting that eNOS haplotypes affect the responsiveness to antihypertensive therapy in PE.

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Section: Discussionmentioning

confidence: 99%

eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension

et al. 2009

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“…31 There is clear evidence of a genetic contribution to the variability in NO formation. 10,18 Interestingly, previous studies reported an association between the C b Glu haplotype and reduced circulating concentrations of NO products. 10,11 Consistent with these findings, our results suggest that this particular eNOS haplotype (C b Glu) is associated with increased susceptibility to hypertension in obese children and adolescents.…”

Section: Discussionmentioning

confidence: 99%

“…10,18 Interestingly, previous studies reported an association between the C b Glu haplotype and reduced circulating concentrations of NO products. 10,11 Consistent with these findings, our results suggest that this particular eNOS haplotype (C b Glu) is associated with increased susceptibility to hypertension in obese children and adolescents. Altogether, these findings suggest that the susceptibility to hypertension in obese children and adolescents could be explained, at least in part, by reduced NO formation, which has been shown in carriers of the C b Glu haplotype.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Indeed, endothelium-derived NO has a major role in vascular homeostasis, causes vasodilation, prevents platelet and leukocyte adhesion, and inhibits vascular smooth muscle cell migration and proliferation. 9 Recent studies have shown that polymorphisms in the gene encoding endothelial nitric oxide synthase (eNOS), the most important enzyme that synthesizes NO in the endothelial cells, affect NO formation, 10,11 drug responses, [12][13][14] and are associated with cardiovascular diseases. 15 Three clinically relevant polymorphisms in this gene have been widely studied: a single-nucleotide polymorphism (SNP) in the promoter region (T À786 C, rs 2070744), an SNP in exon 7 (G894T, rs 1799983) and the variable number of tandem repeats (VNTRs) in intron 4.…”

Section: Introductionmentioning

confidence: 99%

“…To improve the validity of our findings, we have also measured nitrite concentrations in whole-blood samples because nitrite levels reflect endogenous NO formation. 10,12,23 …”

Section: Introductionmentioning

confidence: 99%

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eNOS haplotype associated with hypertension in obese children and adolescents

et al. 2010

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Objective: The aim of our study is to investigate whether genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene (in the promoter region T À786 C, in exon 7 (Glu298Asp) and in intron 4 (4b/4a)) or eNOS haplotypes are associated with hypertension in obese children and adolescents. Methods: We genotyped 175 healthy (controls), 110 normotensive obese and 73 hypertensive obese children and adolescents. Genotypes were determined by Taqman allele discrimination assay and real-time PCR, and by PCR followed by fragment separation by electrophoresis. We compared the distribution of eNOS genotypes, alleles and haplotypes in the three study groups of subjects. We have also measured whole-blood nitrite concentrations. Results: The 4a4a genotype for the intron 4 polymorphism was more common in normotensive obese and hypertensive obese (Po0.01). The AspAsp genotype for Glu298Asp polymorphism was less common in normotensive obese (Po0.02). No significant differences were found in allele distributions for the three eNOS polymorphisms. However, the haplotype combining the C, 4b and Glu variants for the three polymorphisms was more common in hypertensive obese than in normotensive obese or control children and adolescents (odds ratio ¼ 2.28 and 2.79, respectively; 95% confidence interval: 1.31-4.31 and 1.39-5.64, respectively; both Po0.00625). This haplotype was not associated with significantly different nitrite concentrations (P40.05). Conclusions: Our findings suggest that the eNOS haplotype, C b Glu, is associated with hypertension in obese children and adolescents. Further studies examining the possible interactions of eNOS haplotypes with environmental factors and other genetic markers involved in the development of obesity and its complications are warranted.

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