Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative modification of low-density lipoprotein (LDL) leads to formation of the atherogenic molecule oxidized LDL (oxLDL), which is considered to be an important mediator for vascular endothelial dysfunction and atherosclerosis. It is speculated that reduced nitric oxide (NO) release/bioavailability and enhanced release of endothelin-1 (ET-1) may contribute to oxLDL-induced endothelial dysfunction. Estrogen may improve lipid profile and inhibit oxLDL-induced endothelial damage. However, estrogen replacement therapy has been suspended due to uncertainty in benefits versus risk (such as cancer progression) in postmenopausal women. This study was designed to evaluate the effect of a novel phytoestrogen, alpha-zearalanol (alpha-ZAL), on oxLDL-induced effect on NO and ET-1 production in human umbilical vein endothelial cells (HUVEC). HUVEC were incubated with oxLDL (50 microg/mL) for 24 h in the absence or presence of alpha-ZAL (0-1000 nM), 17beta-estradiol (E2, 10 nM), or the E2 receptor antagonist ICI182780 (1 microM). Levels of NO and ET-1 were measured by spectrophotometry and enzymatic immunoassay, respectively. NOS activity was evaluated by conversion of 3H-arginine to 3H-citrulline. Protein and mRNA expression of NOS and ET-1 were measured by Western blot and RT-PCR. Our results indicated that oxLDL significantly reduced NO release and NOS activity, and enhanced ET-1 pro-duction associated with reduced NOS3 (but not NOS2) expression and enhanced ET-1 mRNA expression. All these oxLDL-induced alterations were significantly attenuated or abolished by co-incubation with alpha-ZAL or E2, both through an E2 receptor-dependent mechanism. alpha-ZAL, E2, and ICI182780 had no effect on NO/ET-1 release, NOS activity, or expression of NOS and ET-1. These data suggested that the phytoestrogen alpha-ZAL, like E2, may effectively antagonize oxLDL-induced decrease in NO and increase in ET-1, which may be protective for endothelial function.
 ...
PMID:Phytoestrogen alpha-zearalanol antagonizes oxidized LDL-induced inhibition of nitric oxide production and stimulation of endothelin-1 release in human umbilical vein endothelial cells. 1575 51

Endothelial membrane-bound thrombomodulin is a high affinity receptor for thrombin to inhibit coagulation. We previously demonstrated that the thrombin-thrombomodulin complex restrains cell proliferation mediated through protease-activated receptor (PAR)-1. We have now tested the hypothesis that thrombomodulin transduces a signal to activate the endothelial nitric-oxide synthase (NOS3) and to modulate G protein-coupled receptor signaling. Cultured human umbilical vein endothelial cells were stimulated with thrombin or a mutant of thrombin that binds to thrombomodulin and has no catalytic activity on PAR-1. Thrombin and its mutant dose dependently activated NO release at cell surface. Pretreatment with anti-thrombomodulin antibody suppressed NO response to the mutant and to low thrombin concentration and reduced by half response to high concentration. Thrombin receptor-activating peptide that only activates PAR-1 and high thrombin concentration induced marked biphasic Ca2+ signals with rapid phosphorylation of PLC(beta3) and NOS3 at both serine 1177 and threonine 495. The mutant thrombin evoked a Ca2+ spark and progressive phosphorylation of Src family kinases at tyrosine 416 and NOS3 only at threonine 495. It activated rapid phosphatidylinositol-3 kinase-dependent NO synthesis and phosphorylation of epidermal growth factor receptor and calmodulin kinase II. Complete epidermal growth factor receptor inhibition only partly reduced the activation of phospholipase Cgamma1 and NOS3. Prestimulation of thrombomodulin did not affect NO release but reduced Ca2+ responses to thrombin and histamine, suggesting cross-talks between thrombomodulin and G protein-coupled receptors. This is the first demonstration of an outside-in signal mediated by the cell surface thrombomodulin receptor to activate NOS3 through tyrosine kinase-dependent pathway. This signaling may contribute to thrombomodulin function in thrombosis, inflammation, and atherosclerosis.
 ...
PMID:Endothelial thrombomodulin induces Ca2+ signals and nitric oxide synthesis through epidermal growth factor receptor kinase and calmodulin kinase II. 1612 27

Enzymes involved in the metabolism nitric oxide (NO) and reactive oxygen species (ROS) may play a role for the decreased availability of NO in atherosclerosis. We, therefore, hypothesized that the pattern of gene expression of these enzymes is altered in atherosclerosis. Myocardial tissue from patients with coronary heart disease (CHD) or without CHD (control group) was investigated. The level of enzymes related to NO/ROS metabolism was determined both at mRNA level and protein level by rt-PCR, real-time PCR, and western blot. The expression of NOS1-3 (synthesis of NO), arginase1 (reduction of L-arginine), p22phox (active subunit of NADPH oxidase), GTPCH (rate limiting enzyme for tetrahydrobiopterin), SOD1-3 (scavengers of superoxide anions), PRTMT1-3, and DDAH2 (involved in the metabolism of ADMA) was determined. All enzymes were found to be expressed in human myocardium. NOS isoforms were decreased in CHD in protein level, but only the downregulation of NOS3 expression reached statistical significance. The expression of PRMT1 and PRMT3 was increased. In addition, the expression of DDAH2 was reduced, both theoretically leading to an increase of ADMA concentration. SOD3 was downregulated in tissue from patients with CHD. Taken together, in myocardial tissue from patients with atherosclerosis, the expression of genes increasing ADMA levels is enhanced in contrast to a reduced expression of genes promoting NO synthesis. These results may contribute to the explanation of increased oxidative stress in atherosclerosis on the level of gene expression.
 ...
PMID:Expression of nitric oxide related enzymes in coronary heart disease. 1670 70

It was the objective of this study to investigate the relation between nitric oxide synthase (NOS3) gene polymorphisms, vascular inflammation, endothelial function, and atherosclerosis. We examined the effects of a variable nucleotide tandem repeats (VNTR) in intron 4, G894T in exon 7 and T-786C at the promoter region of NOS3 on i) C-reactive protein (CRP) and macrophage-colony stimulating-factor (MCSF), and ii) augmentation index (AI) measured by pulse-wave analysis , flow-mediated dilation (FMD) of the brachial artery, intima-media thickness (IMT) of the carotid and femoral artery using ultrasonography and ankle-brachial index (ABI) in 122 patients with chronic coronary artery disease (CAD) who underwent coronary angiography. MCSF and CRP were increased in patients withT-786C (77/122) or VNTR (40/122) allele compared to those without (F = 10.8, p = 0.002 and F = 3.8, p = 0.04 for T-786C and F = 3.65, p = 0.04 and F = 3.2 p = 0.049 forVNTR), even after adjustment for traditional risk factors and medication. Patients with combination of VNTR and T-786C (31/122) had higher MCSF or CRP than patients with one or none of these alleles (p < 0.05). Among patients with T-786C, those with MCSF>262 pg/ml or CRP>3.2 mg/l (n = 33/77) had a higher femoral and carotid IMT and number of plaques in the peripheral arteries than those with lower values of these inflammatory indices (p < 0.05). Patients with MCSF >262 pg/ml had also lower FMD and higher Gensini score than those with lower MCSF (p < 0.05). The intron 4-VNTR and T-786C mutation of NOS3 gene enhance the inflammatory process in patients with chronic CAD.
 ...
PMID:Genetic variations of the endothelial nitric oxide synthase gene are related to increased levels of C-reactive protein and macrophage-colony stimulating-factor in patients with coronary artery disease. 1739 38

We investigated the association of 14 polymorphisms in the endothelial nitric oxide synthase gene (NOS3) with ankle brachial index (ABI) in non-Hispanic white hypertensives belonging to hypertensive sibships. Subjects (n=659, mean age 61+/-9 years, 54% women) underwent measurement of ABI using a standard protocol, and the lowest of 4 ABI values was used in the analyses. Non-synonymous SNPs with a minor allele frequency >0.02 and tag SNPs selected based on a measure of linkage disequilibrium (r(2)) were genotyped. We reduced the chance of false positives by testing for replication, randomly selecting 1 hypertensive sib from each sibship to create Subset 1 (n=330) and Subset 2 (n=329). Multivariable linear regression models were used to assess the associations of single NOS3 polymorphisms and haplotypes with ABI after adjustment for covariates (age, sex, body mass index, smoking, total cholesterol, HDL cholesterol, and diabetes). Two specific SNPs in significant LD with each other (rs891512 and rs1808593) were significantly associated with ABI in both subsets. Based on a sliding window approach with a window size of 2, estimated haplotypes from 2 SNP pairs (rs2070744-rs3918226 and rs1808593-rs7830) were also significantly associated with ABI in both subsets. In conclusion, specific NOS3 SNPs and haplotypes were associated with inter-individual variation in ABI, a non-invasive marker of peripheral arterial disease, in replicate subsets of hypertensive subjects. These findings motivate further investigation of the role of NOS3 variants in determining susceptibility to peripheral arterial disease.
Atherosclerosis 2008 Feb
PMID:Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults. 1736 96

As part of the Genetic Epidemiology Network of Arteriopathy study, hypertensive non-Hispanic White sibships were screened using 471 single nucleotide polymorphisms (SNPs) to identify genes influencing coronary artery calcification (CAC) measured by computed tomography. Individuals with detectable CAC and CAC quantity > or =70th age- and sex-specific percentile were classified as having a high CAC burden and compared to individuals with CAC quantity <70th percentile. Two sibs from each sibship were randomly chosen and divided into two data sets, each with 360 unrelated individuals. Within each data set, we applied two machine learning algorithms, Random Forests and RuleFit, to identify the best predictors of having high CAC burden among 17 risk factors and 471 SNPs. Using five-fold cross-validation, both methods had approximately 70% sensitivity and approximately 60% specificity. Prediction accuracies were significantly different from random predictions (P-value<0.001) based on 1,000 permutation tests. Predictability of using 287 tagSNPs was as good as using all 471 SNPs. For Random Forests, among the top 50 predictors, the same eight tagSNPs and 15 risk factors were found in both data sets while eight tagSNPs and 12 risk factors were found in both data sets for RuleFit. Replicable effects of two tagSNPs (in genes GPR35 and NOS3) and 12 risk factors (age, body mass index, sex, serum glucose, high-density lipoprotein cholesterol, systolic blood pressure, cholesterol, homocysteine, triglycerides, fibrinogen, Lp(a) and low-density lipoprotein particle size) were identified by both methods. This study illustrates how machine learning methods can be used in sibships to identify important, replicable predictors of subclinical coronary atherosclerosis.
 ...
PMID:Application of machine learning algorithms to predict coronary artery calcification with a sibship-based design. 1827 Oct 57

Little is known about the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms and the presence of insulin resistance and the early evolution of atherosclerosis in nondiabetic subjects with cardiovascular disease (CAD) and stent implantation. The present study was performed in an attempt to better understand whether metabolic, endothelial, and angiographic findings characteristic of subjects with cardiovascular disease and in-stent restenosis are related to NOS3 variants. This is a case-control study performed from 2002 to 2006. All subjects admitted to the study were recruited in the Nord-Centre of Italy, most from Milan and its surrounding towns. Measures of glucose tolerance, insulin sensitivity, markers of endothelial dysfunction, forearm vasodilation, and adipokine levels were determined and associated to the frequency of two single-nucleotide polymorphisms of NOS3, i.e., Glu298Asp (rs1799983, G/T) and rs753482 (intron 18 A/C). A total of 747 subjects, not known to have diabetes, were evaluated: 333 subjects had asymptomatic CAD, 106 subjects had unstable angina and were evaluated for in-stent restenosis 6 mo after stent placement, and 308 were control subjects. The presence of TT and CC minor alleles was significantly greater in case groups compared with control subjects. At phenotypic level, subjects with the polymorphisms were characterized by hyperinsulinemia and reduced reactive hyperemia, whereas increased leptin and decreased adiponectin levels were present in subjects with restenosis in the presence of reduced minimal lumen diameter and length of stenosis almost doubled. Hyperinsulinemia, endothelial dysfunction, and a more atherogenic profile seem to be peculiar features of subjects with asymptomatic CAD and restenosis carrying NOS3 gene variants.
 ...
PMID:Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis. 1834 7

Aim of the study was to investigate association of gene candidate polymorphisms encoding elements of the renin-angiotensin system and participating in regulation of vascular tone with development of microalbuminuria in patients with hypertensive disease. We examined 93 patients (52 women, 41 men, mean age 58.3+/-1.12 years, mean duration of hypertension 15.6+/-1.16 years) with hypertensive disease. Two patients had arterial hypertension (AG) with I, 22 with II, 63 with III degree of blood pressure (BP) elevation. Thirty four patients smoked, 2 had stroke in anamnesis, 33 had ischemic heart disease, in 58 heredity burdened with cardiovascular diseases was noted. In 38 patients hypertrophy of left ventricular myocardium was revealed. As gene-candidates we considered AGT, ACE, AT2R1, CYP11B2, MTHFR, PPARA, PPARG2, NOS3. Patients with microalbuminuria had significantly higher systolic and diastolic BP levels. Groups did not differ significantly according sex, age, disease duration, glucose level. There were no significant differences in involvement of other target organs - hypertrophy of left ventricular myocardium and atherosclerosis of carotid arteries. Patients with microalbuminuria had significantly higher level of blood cholesterol. Patients with and without microalbuminuria differed only in frequencies of genotypes of polymorphic marker A(-153)G of AT2R1 gene. Genotype AA predisposed to development of nephropathy--odds ratio (OR) 4.71 (95CI 1.78-12.97), while genotype AG was protective (OR 0.20 95%CI 0.07 to 0.56, p=0.031). According to results of multifactorial analysis independent factors affecting increase of risk of development of nephropathy in the studied group were level of systolic BP and carriage of genotype AA of polymorphic marker A(-153)G of AT2R1 gene.
 ...
PMID:[Genetic aspects of development of microalbuminuria in patients with hypertensive disease]. 1907 77

Alzheimer's disease (AD) is a late-onset progressive neurodegenerative disorder which results in the irreversible loss of cortical neurons, particularly in the associative neocortex and hippocampus. AD is the most common form of dementia in the elderly. Apart from the neuronal loss, the pathological hallmarks are extracellular senile plaques, containing the peptide beta-amyloid (Abeta), and neurofibrillary tangles. The Abeta cascade hypothesis remains the main pathogenetic model, as suggested by familiar AD, mainly associated to mutation in amyloid precursor protein and presenilin genes. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. A relationship between genetic and acquired vascular factors and AD has been hypothesized. Many vascular risk factors for AD, such as atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction and trigger AD pathology. A major vascular susceptibility factor gene is the apolipoprotein E gene, found to be associated with sporadic late-onset AD cases. Another interesting vascular susceptibility gene is angiotensin converting enzyme. Other possible genes include VLDL-R, LRP, NOS3, CST3, OLR1, MTHFR, PON1 and VEGF, but many of the related studies have shown conflicting results. In this paper, we review the role of molecular vascular abnormalities and of the "vascular risk" genes supposed to be involved in the pathogenesis of AD, in an attempt to provide a comprehensive picture of what is known about the mechanisms underlying the role of vascular factors in late-onset sporadic AD.
 ...
PMID:The role of vascular factors in late-onset sporadic Alzheimer's disease. Genetic and molecular aspects. 1951 4

Endothelial nitric oxide synthase breaks down nitric oxide and has a key role in blood pressure regulation. Earlier studies have shown associations between single nucleotide polymorphisms (SNPs) in the NOS3 gene and hypertension. Studies also suggest that such associations may vary by dietary fat intake. We investigated associations between the NOS3 Glu298Asp SNP (rs1799983) and hypertension, as well as the interaction between NOS3 genotypes and dietary fat intake using data from baseline examination in white and African American participants in the Atherosclerosis Risk in Community (ARIC) study. Dietary fat intake was measured by a Food Frequency Questionnaire during the baseline examination in 15 792 individuals aged 45-64 years in ARIC study participants. Race-stratified unconditional logistic regression was performed to investigate the association between prevalent hypertension and NOS3 Glu298Asp genotypes. There was no significant interaction between dietary fat intake and NOS3 Glu298Asp genotype with regards to hypertension status in either African Americans or whites (P for interaction=0.3 and 0.4, respectively). We found a significant relationship between NOS3 Glu298Asp and triglycerides in African Americans. We did not find an association between the NOS3 Glu298Asp polymorphism and hypertension, and dietary fat intake did not interact with NOS3 genotypes to influence hypertension. We recommend further exploration of the relationship between NOS3 Glu298Asp and triglycerides in African Americans.
 ...
PMID:Association of NOS3 Glu298Asp SNP with hypertension and possible effect modification of dietary fat intake in the ARIC study. 1996 19


<< Previous 1 2 3 4 Next >>