Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelium-dependent vasorelaxation plays an important role in reduction of blood pressure and is mediated through release of nitric oxide (NO), which is generated by constitutively expressed endothelial nitric oxide synthase (NOS3). Exercise also augments NO release and has been recommended for primary prevention and improvement of hypertension, but individual responses are highly variable. We therefore postulated that genetic polymorphisms of NOS3 might interact with physical activity level to differentially influence blood pressure level. We genotyped 832 healthy Japanese (mean age of 54.4+/-8.6 years, 372 men and 460 women) for a polymorphism of NOS3 in intron 4 (ecNOS4a/b), using the polymerase chain reaction method, and scored their habitual physical activity level by using the rate of energy expenditure per resting metabolic rate through an interview according to a semiquantitative assessment method. Only in the subjects who had the rarer a allele (aa+ba type), systolic blood pressure was found to be inversely correlated with physical activity level (P for linear trend=0.0496, for interaction=0.0071). Eventually, this polymorphism was significantly associated with the prevalence of systolic hypertension only in the subjects who were in the lowest tertile of physical activity level (OR=2.4, 95% CI, 1.1 to 5.6, P for interaction=0.0474). In the present study, we found a significant interaction between the genotype and physical activity level on systolic blood pressure. These results might allow a better understanding of the mechanism to improve hypertension by exercise and to thereby reduce the risk of cardiovascular disease.
Hypertension 2003 Feb
PMID:NOS3 genotype-dependent correlation between blood pressure and physical activity. 1257 7

Deficiency of either neuronal nitric oxide synthase (NOS1) or endothelial nitric oxide synthase (NOS3) leads to cardiac hypertrophy in mice. Loss of both produces concentric left ventricular (LV) remodeling, in which increased wall thickness is accompanied by reduced cavity size. In humans, this phenotype develops in elderly hypertensive patients and independently predicts mortality. Accordingly, we tested the hypothesis that NOS1/3(-/-) mice have reduced longevity compared to either NOS1(-/-) or NOS3(-/-). Survival data on colonies of NOS1(-/-) (n = 295), NOS3(-/-) (n = 525), and NOS1/3(-/-) (n = 331) mice were collected for 2 years. NOS1(-/-) mice had increased mortality compared to NOS3(-/-) (relative risk, RR 2.5, P < 0.001), whereas NOS1/3(-/-) fared significantly worse (RR 7.3, P < 0.001 vs. NOS3(-/-)). Importantly, gender did not affect survival in NOS1(-/-) or NOS3(-/-), but male NOS1/3(-/-) mice had 2-fold increased mortality compared to females. NOS1/3(-/-) mice developed progressive myocyte hypertrophy and interstitial fibrosis with age. NOS1/3(-/-) mice underwent in vivo hemodynamic analysis with a combined pressure-volume catheter to assess age-related cardiovascular changes. Compared with control, NOS1/3(-/-) demonstrated hypertension and hypercontractility at all ages, and developed passive diastolic dysfunction with increasing age. Thus, combined deficiency of NOS1 and NOS3 causes increased mortality, myocyte hypertrophy, and an age-associated increase in ventricular stiffness. These findings suggest that cardiac NO signals may play an essential role in successful cardiac aging.
 ...
PMID:Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice. 1278 81

Association studies give hint for the fact that the risk to develop cardiovascular disorders such as hypertension or coronary heart disease is influenced by the genotype in single nucleotide polymorphisms (SNPs). Considering the close relationship in the pathophysiology of these diseases and erectile dysfunction (ED), the analysis of the association of genotypes in SNPs and ED stands to reason. In an analysis of ED patients and their genotypes in the GNB3 C825T, the ACE I/D and the NOS3 G894T polymorphisms, there was no evidence for influence of the genotypes on the susceptibility to develop ED. At the same time, a significant variation in drug response to sildenafil dependent on the genotypes in the GNB3 C825T and ACE I/D polymorphisms was demonstrated. In the group of GNB3 825C allele carriers, only 50% of patients showed a positive response, while > 90% of the patients genotype TT responded adequately. In parallel, only 50% of ACE D allele carriers showed a positive response to sildenafil in contrast to men genotype II in the ACE I/D polymorphism, who had a response rate of 75%. Considering cardiovascular side effects under sildenafil treatment, it would be interesting to determine if genetic factors have an impact on the side effect profile of this drug.
 ...
PMID:Genetic risk factors for erectile dysfunction and genetic determinants of drug response--on the way to improve drug safety? 1282 46

It has been known for decades that increased dietary intake of salt (NaCl) shortens the life span of rats in a dose-dependent fashion. This review focuses specifically on the recently described biological effect and consequences of increased salt ingestion on the endothelium through a mechanism that is independent of blood pressure. Changes in salt intake are recognized by endothelial cells in the vascular tree and glomeruli through a physical process that promotes a series of signaling events involved in transcriptional regulation of genes that include transforming growth factor-beta1 (TGF-beta1) and the endothelial isoform of nitric oxide synthase (NOS3). A balance is struck between TGF-beta1 and NOS3 as salt intake varies and creates a negative feedback loop, because TGF-beta1 increased expression of NOS3 and NO inhibited production of TGF-beta1 in healthy rats. Changes in this feedback system have been observed in salt-sensitive hypertension and appear to impact end-organ damage, particularly the kidney. The data support an important benefit to reduction of salt intake in the setting of chronic kidney disease.
Hypertension 2004 Feb
PMID:Salt intake, endothelial cell signaling, and progression of kidney disease. 1470 51

Salt-sensitive hypertension is associated with impaired NO/cGMP signaling. We hypothesized that increased superoxide production by NADPH oxidase and altered endothelial NO synthase (NOS3) phosphorylation determine endothelial dysfunction in hypertension. Experiments tested if NO/cGMP signaling and NOS3 serine phosphorylation are decreased and NADPH oxidase activity is increased in mesenteric arteries from deoxycorticosterone acetate (DOCA)-salt rats compared with arteries from placebo rats. Concentration response curves to phenylephrine were performed in mesenteric arteries in the presence and absence of Nomega-nitro-L-arginine (LNA) and antioxidants to determine the influence of basal NO and superoxide production on vascular tone. LNA increased phenylephrine sensitivity in arteries from placebo, but not DOCA-salt rats, regardless of antioxidant treatment. To determine basal cGMP production, mesenteric arteries were incubated with 3-isobutyl-1-methylxanthine in the presence or absence of LNA, sodium nitroprusside (SNP), antioxidants, or tetrahydrobiopterin. NOS-dependent cGMP production was reduced in arteries from DOCA-salt rats compared with arteries from placebo rats and was not restored by acute treatment with antioxidants or tetrahydrobiopterin. SNP-induced cGMP production was similar between groups as was NADPH oxidase activity, measured by lucigenin chemiluminescence, in mesenteric arteries. Expression and phosphorylation of NOS3 were examined by Western blotting. Phosphorylation of NOS3 was decreased in arteries from DOCA-salt rats compared with placebo at serine residues 1179 and 635. These findings indicate that diminished NO/cGMP signaling in mesenteric arteries from DOCA-salt rats is caused by reduced phosphorylation of NOS3 at serine 1179 and serine 635, rather than NO scavenging by superoxide.
Hypertension 2004 May
PMID:Reduced NOS3 phosphorylation mediates reduced NO/cGMP signaling in mesenteric arteries of deoxycorticosterone acetate-salt hypertensive rats. 1499 98

Recent data from animal models indicate that the eNOS null mice present a phenotype that resemble the human metabolic syndrome (hypertension, insulin resistance and hypertriglyceridemia). In this work, we have studied whether NOS3 gene, previously related to endothelial dysfunction, might have a role in metabolic syndrome susceptibility in hypertensive patients. To carry out the study, we genotyped 105 hypertensive patients < or = 60 years old with two polymorphisms of NOS3 gene: 1132 T>C and 7164 G>T (GeneBank:AF519768.1). To check the allelic frequency of these polymorphisms in our geographical area, we also genotyped 94 unselected healthy controls (control group). To perform sample genotyping, we designed a novel FRET system coupled to real time PCR. There were no differences in genotypic distribution or allelic frequency between hypertensive patients and the control group. However, we observed that 786CC genotype was significantly more frequent in hypertensive patients with metabolic syndrome than in those without the syndrome (p=0.0022). When both polymorphisms were analyzed, we identified the 786C894G as the risk haplotype for metabolic syndrome susceptibility (p=0.011). These data suggest a role of the NOS3 gene in the pathogenesis of metabolic syndrome in hypertensive patients.
 ...
PMID:Association of NOS3 gene with metabolic syndrome in hypertensive patients. 1526 39

Studies on the associations between the nitric oxide synthase gene (NOS3) Glu298Asp polymorphism and hypertension status or blood pressure (BP) levels have had inconsistent results. Potential moderating influences of ethnicity, sex, and obesity on the effects of the NOS3 polymorphism have not been examined. We evaluated the influence of these factors on associations between the NOS3 polymorphism, nitric oxide metabolites (NOx), and hemodynamics at rest and during stress. Subjects were 235 African American (AA) and 262 European American (EA) young adults (18.5+/-2.6 years). Hemodynamic measurements and blood samples for NOx assays were taken before and after a competitive video game challenge. Glu298Asp polymorphism was detected by polymerase chain reaction-restriction enzyme digestion assay. A regression model was built using genotypes, ethnicity, sex, and obesity (body mass index >85th percentile) and their interactions controlling for age; 20.1% of AAs and 49.8% of EAs were carriers of the Asp allele. AAs, regardless of obesity status, exhibited high diastolic blood pressure (DBP) reactivity unless they were nonobese and noncarriers of the Asp allele. EAs exhibited lower DBP reactivity unless they were obese Asp allele carriers. AA nonobese carriers exhibited the greatest total peripheral resistance reactivity. Obese Asp allele carriers exhibited the greatest increases in cardiac output and the greatest decrease in NOx to the stressor. Results indicate the importance of examining impact of BP control-related genetic polymorphisms within the context of moderating factors such as adiposity and ethnicity.
Hypertension 2004 Dec
PMID:Effects of NOS3 Glu298Asp polymorphism on hemodynamic reactivity to stress: influences of ethnicity and obesity. 1550 16

Epidemiological studies have shown increased incidence of hypertension and coronary artery disease in growth-restricted fetuses during their adult life. A novel animal model was used to test the hypothesis regarding the role of an abnormal uterine environment in fetal programming of adult vascular dysfunction. Mice lacking a functional endothelial nitric oxide synthase (NOS3-/-KO, where KO is knockout) and wild-type (WT) mice (NOS3+/+WT) were crossbred to produce homozygous NOS3-/-KO, maternally derived heterozygous (NOS3+/-mat, mother with NOS3 deficiency), paternally derived heterozygous (NOS3+/-pat, normal mother), and NOS3+/+WT litters. Number of fetuses per litter was smaller in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Adult female mice from these litters (7-8 wk old) were killed, and ring preparations of carotid and mesenteric arteries were mounted in a wire myograph to evaluate the passive and reactive vascular characteristics. Slope of the length-tension plot (a measure of vascular compliance) was increased, and optimal diameter (as calculated by Laplace equation) was decreased in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Acetylcholine caused vasorelaxation in NOS3+/-pat and NOS3+/+WT and contraction in NOS3-/-KO and NOS3+/-mat mice. Responses to phenylephrine and Ca2+ were increased in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Relaxation to isoproterenol was decreased in NOS3-/-KO and NOS3+/-mat vs. NOS3+/-pat and NOS3+/+WT mice. Abnormalities in the passive and reactive in vitro vascular properties seen in NOS+/-mat that developed in a NOS3-deficient maternal/uterine environment compared with the genetically identical NOS3+/-pat mice that developed in a normal environment are the first direct evidence in support of a role for uterine environment in determining vascular function in later life.
 ...
PMID:Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase. 1562 80

Insulin resistance is a determinant of blood pressure variation and risk factor for hypertension. Because insulin resistance and blood pressure cosegregate in Mexican American families, we thus investigated the association between variations in 9 previously reported hypertension genes (ACE, AGT, AGTRI, ADDI, NPPA, ADDRB2, SCNN1A, GNB3, and NOS3) and insulin resistance. Families were ascertained via a coronary artery disease proband in the Mexican American Coronary Artery Disease Project. Individuals from 100 Mexican American families (n=656) were genotyped for 14 polymorphisms in the 9 genes and all adult offspring and offspring spouses were phenotyped for insulin sensitivity by hyperinsulinemic euglycemic clamp (n=449). AGT M235T and NOS3 A(-922)G and E298D polymorphisms were significantly associated with insulin sensitivity (P=0.018, 0.036, 0.039) but were not significant after adjusting for body mass index. ADD1 G460W was associated with insulin sensitivity only after adjusting for body mass index. The NPPA T2238C and SCNN1A A663T were associated with decreased fasting insulin levels after adjusting for body mass index (P=0.015 and 0.028). In conclusion, AGT, NOS3, NPPA, ADRB2, ADD1, and SCNN1A may well be genetic markers for insulin resistance, and adiposity was a potential modifier for only some gene/trait combinations. Our data support the hypothesis that genes in the blood pressure pathway may play a role in insulin resistance in Mexican Americans.
Hypertension 2005 Apr
PMID:Hypertension genes are genetic markers for insulin sensitivity and resistance. 1569 55

Association of polymorphic markers G7831A of ACE gene, Lys198Asn of endothelin-1 (EDN1) gene, and 4a/4b of NOS3 gene with characteristics of structure and function of the left ventricle was studied in 70 (31 men and 39 women) natives of Yakutia with hypertension. Mean age of patients was 48.3+/-0.74 years, duration of hypertension -- 12.4+/-0.99 years; 60 (85.7%), 7 (10%) and 3 (4.3%) patients had III, II and I degree of hypertension, respectively. Polymerase chain reaction was used for identification of alleles of polymorphic markers G7831A of ACE gene, Lys198Asn of EDN1 gene, and 4a/4b of NOS3 gene. Polymorphic marker G7831A of ACE gene was not associated with severity of hypertrophy of left ventricular myocardium as well as with state of systolic and diastolic left ventricular function. Patients with allele Asn of EDN1 gene in the genotype had significantly lower value of peak A integral of trans-mitral blood flow. Patients with allele 4a of NOS3 gene had thicker left ventricular walls, greater left ventricular myocardial mass and mass index.
 ...
PMID:[Angiotensin converting enzyme, NO-synthase, and endothelin-1 genes and left ventricular hypertrophy in natives of Yakutia with hypertensive disease]. 1569 38


<< Previous 1 2 3 4 5 6 7 8 Next >>