967 resultados para eNOS haplotype


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Impairment of endothelial nitric oxide synthase (eNOS) activity is implicated in the pathogenesis of endothelial dysfunction in many diseases including ischaemic stroke. The modulation of eNOS during and/or following ischaemic injury often represents a futile compensatory mechanism due to a significant decrease in nitric oxide (NO) bioavailability coupled with dramatic increases in the levels of reactive oxygen species that further neutralise NO. However, applications of a number of therapeutic agents alone or in combination have been shown to augment eNOS activity under a variety of pathological conditions by potentiating the expression and/or activity of Akt/eNOS/NO pathway components. The list of these therapeutic agents include NO donors, statins, angiotensin-converting enzyme inhibitors, calcium channel blockers, phosphodiesterase-3 inhibitors, aspirin, dipyridamole and ellagic acid. While most of these compounds exhibit anti-platelet properties and are able to up-regulate eNOS expression in endothelial cells and platelets, others suppress eNOS uncoupling and tetrahydrobiopterin (an eNOS stabiliser) oxidation. As the number of therapeutic molecules that modulate the expression and activity of eNOS increases, further detailed research is required to reveal their mode of action in preventing and/or reversing the endothelial dysfunction.

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Analyses of high-density single-nucleotide polymorphism (SNP) data, such as genetic mapping and linkage disequilibrium (LD) studies, require phase-known haplotypes to allow for the correlation between tightly linked loci. However, current SNP genotyping technology cannot determine phase, which must be inferred statistically. In this paper, we present a new Bayesian Markov chain Monte Carlo (MCMC) algorithm for population haplotype frequency estimation, particulary in the context of LD assessment. The novel feature of the method is the incorporation of a log-linear prior model for population haplotype frequencies. We present simulations to suggest that 1) the log-linear prior model is more appropriate than the standard coalescent process in the presence of recombination (>0.02cM between adjacent loci), and 2) there is substantial inflation in measures of LD obtained by a "two-stage" approach to the analysis by treating the "best" haplotype configuration as correct, without regard to uncertainty in the recombination process. Genet Epidemiol 25:106-114, 2003. (C) 2003 Wiley-Liss, Inc.

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The average UK adult consumes less than three portions of fruit and vegetables daily, despite evidence to suggest that consuming five portions daily could help prevent chronic diseases. It is recommended that fruit juice should only count as one of these portions, as juicing removes fibre and releases sugars. However, fruit juices contain beneficial compounds such as vitamin C and flavonoids and could be a useful source of dietary phytochemicals. Two randomised controlled cross-over intervention studies investigating the effects of chronic and acute consumption of commercially-available fruit- and vegetable-puree-based drinks (FVPD) on bioavailability, antioxidant status and CVD risk factors are described. Blood and urine samples were collected during both studies and vascular tone was measured using laser Doppler imaging. In the chronic intervention study FVPD consumption was found to significantly increase dietary carotenoids (P = 0.001) and vitamin C (P = 0.003). Plasma carotenoids were increased (P = 0.001), but the increase in plasma vitamin C was not significant. There were no significant effects on oxidative stress, antioxidant status and other CVD risk factors. In the acute intervention study FVPD were found to increase total plasma nitrate and nitrite (P = 0.001) and plasma vitamin C (P = 0.002). There was no effect on plasma lipids or uric acid, but there was a lower glucose and insulin peak concentration after consumption of the FVPD compared with the sugar-matched control. There was a trend towards increased vasodilation following both chronic and acute FVPD consumption. All volunteers were retrospectively genotyped for the eNOS G298T polymorphism and the effect of genotype on the measurements is discussed. Overall, there was a non-significant trend towards increased endothelium-dependent vasodilation following both acute and chronic FVPD consumption. However, there was a significant time x treatment effect (P < 0.05) of acute FVPD consumption in individuals with the GG variant of the eNOS gene.

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A nitric oxide synthase (NOS)-like activity has been demonstrated in human red blood cells (RBCs), but doubts about its functional significance, isoform identity and disease relevance remain. Using flow cytometry in combination with the NO-imaging probe DAF-FM we find that all blood cells form NO intracellularly, with a rank order of monocytes > neutrophils > lymphocytes > RBCs > platelets. The observation of a NO-related fluorescence within RBCs was unexpected given the abundance of the NO-scavenger oxyhemoglobin. Constitutive normoxic NO formation was abolished by NOS inhibition and intracellular NO scavenging, confirmed by laser-scanning microscopy and unequivocally validated by detection of the DAF-FM reaction product with NO using HPLC and LC-MS/MS. Employing immunoprecipitation, ESI-MS/MS-based peptide sequencing and enzymatic assay we further demonstrate that human RBCs contain an endothelial NOS (eNOS) that converts L-3H-Arginine to L-3H-Citrulline in a Ca2+/Calmodulin-dependent fashion. Moreover, in patients with coronary artery disease, red cell eNOS expression and activity are both lower than in age-matched healthy individuals and correlate with the degree of endothelial dysfunction. Thus, human RBCs constitutively produce NO under normoxic conditions via an active eNOS isoform the activity of which is compromised in patients with coronary artery disease.

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In barley, variation in the requirement for vernalization (an extended period of low temperature before flowering can occur) is determined by the VRN-H1, -H2 and -H3 loci. In European cultivated germplasm, most variation in vernalization requirement is accounted for by alleles at VRN-H1 and VRN-H2 only, but the range of allelic variation is largely unexplored. Here we characterise VRN-H1 and VRN-H2 haplotypes in 429 varieties representing a large portion of the acreage sown to barley in Western Europe over the last 60 years. Analysis of genotype, intron I sequencing data and growth habit tests identified three novel VRN-H1 alleles and determined the most frequent VRN-H1 intron I rearrangements. Combined analysis of VRN-H1 and VRN-H2 alleles resulted in the classification of seventeen VRN-H1/VRN-H2 multi-locus haplotypes, three of which account for 79% of varieties. The molecular markers employed here represent powerful diagnostic tools for prediction of growth habit and assessment of varietal purity. These markers will also allow development of germplasm to test the behaviour of individual alleles with the aim of understanding the relationship between allelic variation and adaptation to specific agri-environments.

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BACKGROUND: The gene encoding for uncoupling protein-1 (UCP1) is considered to be a candidate gene for type 2 diabetes because of its role in thermogenesis and energy expenditure. The objective of the study was to examine whether genetic variations in the UCP1 gene are associated with type 2 diabetes and its related traits in Asian Indians. METHODS: The study subjects, 810 type 2 diabetic subjects and 990 normal glucose tolerant (NGT) subjects, were chosen from the Chennai Urban Rural Epidemiological Study (CURES), an ongoing population-based study in southern India. The polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies. RESULTS: The three polymorphisms, namely -3826A-->G, an A-->C transition in the 5'-untranslated region (UTR) and Met229Leu, were not associated with type 2 diabetes. However, the frequency of the A-C-Met (-3826A-->G-5'UTR A-->C-Met229Leu) haplotype was significantly higher among the type 2 diabetic subjects (2.67%) compared with the NGT subjects (1.45%, P < 0.01). The odds ratio for type 2 diabetes for the individuals carrying the haplotype A-C-Met was 1.82 (95% confidence interval, 1.29-2.78, P = 0.009). CONCLUSIONS: The haplotype, A-C-Met, in the UCP1 gene is significantly associated with the increased genetic risk for developing type 2 diabetes in Asian Indians.

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Our objective was to investigate whether the presence of Glu298Asp polymorphism in the endothelial NO synthase (eNOS) gene differentially affects the postprandial blood pressure response to dietary nitrate-rich beetroot bread. A randomised, single-blind, controlled, crossover acute pilot study was performed in 14 healthy men (mean age: 34±9 years) who were retrospectively genotyped for Glu298Asp polymorphism (7GG; T carriers 7). Volunteers were randomised to receive 200 g beetroot-enriched bread (1.1 mmol nitrate) or control bread (no beetroot; 0.01 mmol nitrate) on two separate occasions 10 days apart. Baseline and incremental area under the curve of blood pressure and NOx (nitrate/nitrite) were measured for a 6-h postprandial period. A treatment × genotype interaction was observed for diastolic blood pressure (P<0.02), which was significantly lower in T carriers (P<0.01) after consumption of beetroot bread compared with control bread. No significant differences were observed in the GG group. The beneficial diastolic blood pressure reduction was observed only in the T carriers of the Glu298Asp polymorphism in the eNOS gene after consumption of nitrate-rich beetroot bread. These data require confirmation in a larger population group.

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Background Emerging cellular markers of endothelial damage and repair include endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) respectively. Effects of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) and influence of genetic background on these markers are not known. Objective This study investigated the effects of fish oil supplementation on both classical and novel markers of endothelial function in subjects prospectively genotyped for the Asp298 eNOS polymorphism and at moderate risk of CVD. Design 84 subjects with moderate risk of CVD (n=40 GG and n=44 GT/TT) completed a randomized, double-blind, placebo-controlled, 8-week cross-over trial of fish oil supplementation providing 1.5 g/d LC n-3 PUFA. Effects of genotype and fish oil supplementation on the blood lipid profile, inflammatory markers, vascular function (EndoPAT) and numbers of circulating EPCs and EMP (flow cytometry) were assessed. Results There was no significant effect of fish oil supplementation on blood pressure, plasma lipids or plasma glucose, although there was a trend (P = 0.069) towards a decrease in plasma TG concentration after FO supplementation compared to placebo. GT/TT subjects tended to have higher levels of total cholesterol and LDL-cholesterol, but vascular function was not affected by either treatment or eNOS genotype. Biochemical markers of endothelial function were also unaffected by treatment and eNOS genotype. In contrast, there was a significant effect of fish oil supplementation on cellular markers of endothelial function. Fish oil supplementation increased numbers of EPCs and reduced numbers of EMPs relative to the placebo, potentially favouring maintenance of endothelial integrity. There was no influence of genotype for any of the cellular markers of endothelial function, indicating that the effects of fish oil supplementation were independent of eNOS genotype. Conclusions Emerging cellular markers of endothelial damage, integrity and repair appear to be sensitive to potentially beneficial modification by dietary n-3 PUFA.

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The polymorphisms of endothelial nitric oxide synthase (eNOS) are associated with reduced eNOS activity. Aerobic exercise training (AEX) may influence resting nitric oxide (NO) production, oxidative stress and blood pressure. The purpose of this study was to investigate the effect of AEX on the relationship among blood pressure, eNOS gene polymorphism and oxidative stress in pre-hypertensive older people. 118 pre-hypertensive subjects (59 +/- A 6 years) had blood samples collected after a 12 h overnight fast for assessing plasma NO metabolites (NOx) assays, thiobarbituric acid reactive substances (T-BARS) and superoxide dismutase activity (ecSOD). eNOS polymorphism (T-786C and G-894T) was done by standard PCR methods. All people were divided according to the genotype results (G1: TT/GG, G2: TT/GT + TT, G3: TC + CC/GG, G4: TC + CC/GT + TT). All parameters were measured before and after 6 months of AEX (70% of VO(2 max)). At baseline, no difference was found in systolic and diastolic blood pressure, ecSOD and T-BARS activity. Plasma NOx levels were significantly different between G1 (19 +/- A 1 mu M) and G4 (14.2 +/- A 0.6 mu M) and between G2 (20.1 +/- A 1.7 mu M) and G4 (14.2 +/- A 0.6 mu M). Therefore, reduced NOx concentration in G4 group occurred only when the polymorphisms were associated, suggesting that these results are more related to genetic factors than NO-scavenging effect. After AEX, the G4 increased NOx values (17.2 +/- A 1.2 mu M) and decreased blood pressure. G1, G3 and G4 decreased T-BARS levels. These results suggest the AEX can modulate the NOx concentration, eNOS activity and the relationship among eNOS gene polymorphism, oxidative stress and blood pressure especially in C (T-786C) and T (G-894T) allele carriers.

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Statins have pleiotropic effects, including endothelial nitric oxide synthase (eNOS) upregulation and increased nitric oxide formation, which can be modulated by a genetic polymorphism in the promoter region of the eNOS gene (T-786C). Here, we report our investigation of whether this polymorphism modulates the effects of atorvastatin on the fluidity of erythrocyte membranes. We genotyped 200 healthy subjects (males, 18-60 years of age) and then randomly selected 15 of these with the TT genotype and 15 with the CC genotype to receive placebo or atorvastatin (10 mg/day oral administration) for 14 days. Cell membrane fluidity was evaluated by electron paramagnetic resonance (EPR) and spin-labeling method. The EPR spectra were registered on a VARIAN-E4 spectrometer. Thiobarbituric acid-reactive species (TBA-RS) and plasma membrane cholesterol were determined in the erythrocytes. Atorvastatin reduced membrane fluidity in CC subjects (P < 0.05) but not in those with the TT genotype (P > 0.05). While no significant differences were found in plasma membrane cholesterol concentrations, higher TBA-RS concentrations were found in the CC subjects than in the TT subjects (P < 0.05). These findings suggest that a short treatment with atorvastatin is disadvantageous to subjects with the CC genotype for the T-786C polymorphism compared to those with TT genotype, at least in terms of the hemorheological properties of erythrocytes.