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

Several key genes involved in cholesterol metabolism are known to be directly regulated by cholesterol. The possible indirect effect, however, of increased levels of cellular cholesterol on gene expression and its possible role in cholesterol metabolism and atherosclerosis has not been thoroughly explored. In order to determine the overall effect of cholesterol on gene expression, we isolated differentially expressed genes from a PCR-based subtraction library prepared from the liver of chow-fed and cholesterol-fed rabbits. A total of nine upregulated and four down-regulated cDNA fragments were isolated. As determined by Northern blot analysis, the expression of the isolated cDNAs began to change as early as the first week on the cholesterol-rich diet or as late as 4 weeks, which corresponded with hepatic cholesterol accumulation. Three of the cDNAs were identified by DNA sequence homology, whereas the remaining cDNAs had no significant homology match. CYP1A1, a cytochrome P450 isoenzyme, was found to be down-regulated in hepatocytes by cholesterol feeding. Osteopontin and Mac-2, which are produced by macrophages, were found to be up-regulated in Kupffer cells by cholesterol feeding. Overall these results demonstrate the usefulness of the subtraction library approach for identifying new candidate genes for exploring the pathogenesis of atherosclerosis.
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PMID:Identification of novel differentially expressed hepatic genes in cholesterol-fed rabbits by a non-targeted gene approach. 775 18

Epidemiological studies have strongly implicated active and passive smoking with increased risk of cardiovascular diseases. The present study was performed to determine if exposure to sidestream cigarette smoke (SSCS), a surrogate of environmental tobacco smoke, promotes atherogenesis in a mouse model of human atherosclerosis. Female ApoE-deficient mice, maintained on a Western diet, were exposed to SSCS in a whole-body exposure chamber for a total of 6 h each day, 5 days a week for 7, 10 and 14 weeks. Animals exposed to filtered ambient air served as controls. Elevated concentrations of blood carboxyhemoglobin and pulmonary CYP1A1 ascertained effective exposure of animals to SSCS. There were no consistent changes in serum concentrations of cholesterol between control and SSCS-exposed mice. Morphometric assessment of grossly discernible lesions covering the intimal area of aorta showed remarkable increases in SSCS-exposed mice at all three exposure durations studied. Increases in the lesion area defined by en face measurements were accompanied by parallel increases in the levels of esterified and unesterified cholesterol in the aortic tissues of SSCS mice. These results clearly demonstrate promotion of atherosclerotic lesion development by tobacco smoke in an atherosclerosis-susceptible mouse model.
Atherosclerosis 2001 May
PMID:Sidestream cigarette smoke accelerates atherogenesis in apolipoprotein E-/- mice. 1136 96

Potential pharmacological applications in the areas of oncology, dermatology, diabetes, and atherosclerosis of synthetic analogs of retinoic acid that target a specific nuclear receptor and/or biological response have generated great interest in the development of new retinoid and rexinoid drugs. The pan-retinoic acid receptor antagonist AGN 193109 has been previously reported to elevate CYP1A1 levels, implicating the aryl hydrocarbon receptor (AhR) as an additional target for this retinoid. AhR is a cytosolic ligand-dependent transcription factor that, in conjunction with the AhR nuclear translocator (Arnt), binds to dioxin response elements (DREs) located in the promoter region of target genes, such as CYP1A1, and induces their transcription. The purpose of these studies was to determine whether additional synthetic retinoids were capable of elevating CYP1A1 levels and to examine the mechanism of this increase in CYP1A. Two additional retinoids, AGN 190730 and AGN 192837, were found to be potent inducers of DRE-driven transcriptional activity; AGN 190730 was the most potent. Moreover, electrophoretic mobility-shift assays demonstrate that AGN 190730 can transform AhR into its active DNA recognition form. In addition, trypsin digestion of AGN 190730-treated AhR reveals a conformational change in the protein similar to the conformational change of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-bound AhR. Finally, competitive binding studies demonstrate that AGN 190730 can inhibit the binding of TCDD to AhR. The sum of the data demonstrates that some synthetic retinoids in addition to activating the retinoic acid receptor/retinoid X receptor pathway are capable of binding to AhR and activating the AhR/Arnt pathway.
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PMID:Unique property of some synthetic retinoids: activation of the aryl hydrocarbon receptor pathway. 1180 58

Atherosclerosis and carcinogenesis may share some common mechanisms of the genotoxic action of exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs). The main objective of this study was to test the hypothesis that "bulky" aromatic DNA-adducts in smooth muscle cells (SMCs) of thoracic aortas taken at autopsy from sudden and accidental death male subjects, aged between 30 and 60 years (N=133), are associated with the stage of atherosclerosis. The subjects with severe atherosclerotic damage were treated as "Cases" (N=66). The subjects meeting diagnostic criteria for slight and moderate total atherosclerotic body damage were treated as "Controls" (N=67). An additional objective of the study was to evaluate the effect of known atherogenic risk factors and possible modifiers of atherosclerotic changes, such as age, smoking, plasma lipid and antioxidant vitamin levels and some genetic susceptibility markers, e.g. polymorphisms of GSTM1, GSTT1, NAT2, CYP1A1 or apolipoprotein E (APO E) genes. We found significantly higher DNA-adduct levels in "Cases" as compared with "Controls" (2.11+/-1.07 adducts/10(8) nucleotides versus 1.49+/-0.55 adducts/10(8) nucleotides, P<0.001). "Cases" were significantly older and had elevated heart weight and plasma cholesterol levels and a higher frequency of overweight subjects as compared with "Controls". No significant differences in DNA-adduct levels between smokers and non-smokers within either group were detected. Multivariate logistic regression revealed that the "bulky" aromatic DNA-adducts, which are the most likely related to environmental exposure to genotoxic chemicals, remain a statistically significant predictor of the stage of atherosclerosis (OR=3.76, 95% CI=1.54-9.18, P=0.004) even after adjustment for age, smoking, obesity, heart weight and genetic susceptibility markers (GSTT1 and CYP1A1-MspI polymorphisms) that were also significant predictors. The fact that the "bulky" aromatic DNA-adduct levels predict the progression of atherosclerosis independently of smoking indicates that the formation of atherosclerotic plaques may also be initiated by environmental exposures other than tobacco smoke.
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PMID:DNA-adducts and atherosclerosis: a study of accidental and sudden death males in the Czech Republic. 1193 43

CYP1A1, is one of the key detoxifying enzymes catabolizing cigarette smoking derived toxins and may be relevant to smoking-induced atherogenesis. Recently a CYP1A1 MspI polymorphism at the 3'-flanking region of the gene has been found to be associated with smoking related cancer risk and may, therefore, also be associated with vascular disease. To explore this, we investigated interactive effects between smoking and the CYP1A1 MspI polymorphism on coronary artery disease (CAD), diabetes and hypertension in 701 patients (aged < or =65 years) consecutively referred to Eastern Heart Clinic for angiographic investigation. The frequencies of the TT (80.2%), TC (17.7%) and CC (2.1%) genotypes were in Hardy-Weinberg equilibrium with the rare C allele frequency 0.11. The C allele carriers had an increased risk for triple vessel disease (three major epicardial coronary arteries with > or =50% luminal obstruction, OR, 3.44; 95%CI, 1.46-8.09; P=0.0046) in light smokers (< or =20 packyears). We further identified an interactive effect between smoking, the CYP1A1 MspI polymorphism and type 2 diabetes (chi(2)=9.508, P=0.002). The C allele carriers who were smokers had an increased risk of diabetes (OR, 2.44; 95%CI, 1.32-4.49; P=0.0059). Our study suggests that CYP1A1 may participate in the pathogenesis of atherosclerosis and in the development of diabetes and its vascular complications. The presence of the rare C allele of the CYP1A1 gene in smokers may enhance predisposition to severe CAD and type 2 diabetes. These findings contribute to the understanding of cardiovascular risk and to smoking related vascular disease.
Atherosclerosis 2002 Jun
PMID:Effect of CYP1A1 MspI polymorphism on cigarette smoking related coronary artery disease and diabetes. 1199 59

So-called coplanar polychlorinated biphenyls (PCBs), as well as other environmental contaminants that are aryl hydrocarbon receptor (AhR) agonists, may compromise the normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. To test this hypothesis, porcine endothelial cells were exposed to PCB 153 and to three coplanar PCBs (PCB 77, PCB 126, or PCB 169). In contrast to PCB 153, which is not a ligand for the Ah receptor (AhR), all coplanar PCBs disrupted endothelial barrier function. All coplanar PCBs increased expression of the CYP1A1 gene, oxidative stress (DCF fluorescence), and the DNA-binding activity of nuclear factor kappaB (NF-kappaB). PCB-induced oxidative stress was concentration-dependent, with PCB 126 exhibiting a maximal response at the lowest concentration (0.5 microM) tested. The increase in NF-kappaB-dependent transcriptional activity was confirmed in endothelial cells by a luciferase reporter gene assay. In contrast to PCB 153, coplanar PCBs that are AhR ligands increased endothelial production of interleukin-6. At 3.4 microM, expression of the adhesion molecule VCAM-1 was most sensitive to PCB 77 and 169. We also provide in vivo evidence, suggesting that binding to the AhR is critical for the proinflammatory properties of PCBs. Twenty hours after a single administration of PCB 77, VCAM-1 expression was increased only in wild-type mice, while mice lacking the AhR gene showed no increased staining for VCAM-1. These data provide evidence that coplanar PCBs, agonists for the AhR, and inducers of cytochrome P450 1A1, produce oxidative stress and an inflammatory response in vascular endothelial cells. An intact AhR may be necessary for the observed PCB-induced responses. These findings suggest that activation of the AhR can be an underlying mechanism of atherosclerosis mediated by certain environmental contaminants.
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PMID:Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence. 1207 26

Benzo[a]pyrene (BP), a polycylic aromatic hydrocarbon (PAH), is a potent atherogen and carcinogen in laboratory animals. Since genotoxic mechanisms may contribute to the development of atherosclerosis by PAHs, we have tested the hypotheses that: 1) BP induces DNA adducts in mouse aortic smooth muscle cells (SMCs); 2) 3-hydroxybenzo[a]pyrene (3-OH-BP) and benzo[a]pyrene-3,6-quinone (BPQ) are proximate genotoxic metabolites; and 3) cytochrome P4501B1 (CYP1B1) mediates the activation of BP and its metabolites to ultimate genotoxic intermediates. Cultured mouse aortic SMCs were treated with BP, 3-OH-BP, or BPQ for 24 h, and DNA adduct formation was analyzed by (32)P-postlabeling. In some experiments, cells were pretreated with the CYP1B1 inhibitor 1-ethynylpyrene (EP) prior to exposure to BP or its metabolites. BP, 3-OH-BP, and BPQ induced formation of several DNA adducts that were not observed in dimethylsulfoxide-treated cells. Re- and cochromatography experiments indicated that 3-OH-BP and BPQ were proximate genotoxic metabolites of BP. DNA adduct formation was strongly inhibited by EP, a specific inhibitor of CYP1B1. BP treatment of SMCs resulted in induction of aryl hydrocarbon hydroxylase (AHH) activity and CYP1B1, but not CYP1A1, apoprotein. EP also blocked AHH induction by BP. In conclusion, the results of this study support the hypothesis that in SMCs, which are target sites for the development of atherosclerosis, the major bioactivation pathway of BP entails CYP1B1-mediated formation of the 3-OH-BP and BPQ, which are proximate genotoxic metabolites that may in turn get transformed to ultimate DNA-binding metabolites, which may contribute to atherogenesis by PAHs.
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PMID:Role of cytochrome P4501B1 in benzo[a]pyrene bioactivation to DNA-binding metabolites in mouse vascular smooth muscle cells: evidence from 32P-postlabeling for formation of 3-hydroxybenzo[a]pyrene and benzo[a]pyrene-3,6-quinone as major proximate genotoxic intermediates. 1264 94

Cigarette smoking as an addictive habit has accompanied human beings for more than 4 centuries. It is also one of the most potent and prevalent environmental health risks human beings are exposed to, and it is responsible for more than 1000 deaths each day in the United States. With recent research progress, it becomes clear that cigarette smoking can cause almost all major diseases prevalent today, such as cancer or heart disease. These detrimental effects are not only present in active smokers who choose the risk, but also to innocent bystanders, as passive smokers, who are exposed to cigarettes not-by-choice. While the cigarette-induced harm to human health is indiscriminate and severe, the degree of damage also varies from individual to individual. This intersubject variability in cigarette-induced pathologies is partly mediated by genetic variants of genes that may participate in detoxification process, eg, cytochrome P450 (CYP), cellular susceptibility to toxins, such as p53, or disease development. Through population studies, we have learned that certain CYP1A1 variants, such as Mspl polymorphism, may render the carriers more susceptible to cigarette-induced lung cancer or severe coronary atherosclerosis. The endothelial nitric oxide synthase intron 4 rare allele homozygotes are more likely to have myocardial infarction if they also smoke. In vitro experimental approach has further demonstrated that cigarettes may specifically regulate these genes in genotype-dependent fashion. While we still know little about genetic basis and molecular pathways for cigarette-induced pathological changes, understanding these mechanisms will be of great value in designing strategies to further reduce smoking in targeted populations, and to implement more effective measures in prevention and treatment of cigarette-induced diseases.
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PMID:Genetic influence on cigarette-induced cardiovascular disease. 1270 94

There is little doubt that cigarette smoking remains a major environmental health risk that humans are facing in the twenty-first century. Cigarette smokers are more likely to develop many forms of diseases than nonsmokers, including cancers and vascular diseases. With the availability of the human genome sequence, we become more aware of the genetic contributions to these common diseases, especially the interactive relations between environmental factors (e.g., smoking) and genes on disease susceptibility, development, and prognosis. Although smoking is responsible for up to 30% of pancreatic cancers and about 10% of cases are ascribed to genetic reasons, some genetic variants do not predispose carriers to disease development unless they are exposed to a specific adverse environment such as smoking. This smoke-gene interaction could potentially be responsible for most of the cases. Certain polymorphisms in genes such as CYP1A1 have been shown particularly sensitive to smoking-induced pathogenesis, including pancreatic cancer and atherosclerosis. We found that individuals with CYP1A1 CC genotype had a more than three fold increase in risk for severe coronary atherosclerosis when they smoked. Patients with endothelial nitric oxide synthase (eNOS) intron 4 27 repeat homozygotes were more likely to develop severe coronary stenosis when they smoked. On the other hand, DNA variants at the eNOS gene also dictate how smoking affects the expression of eNOS. We showed that GSTM1 deficiency was not involved in smoking-induced vascular diseases, but p53 polymorphisms tended to modify the disease severity in smokers. We are still at an early stage of defining the pairs and mechanisms of smoke-gene interaction, and this etiologic mechanism may hold great potential for risk assessment, treatment strategy, and prognostic predictions.
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PMID:Smoking-gene interaction and disease development: relevance to pancreatic cancer and atherosclerosis. 1569 95

Polycyclic aromatic hydrocarbons (PAHs) have been known to induce atherosclerosis. It has been reported that the metabolic activation of PAHs by cytochrome P450 (CYP) is an important step for PAH-induced atherosclerosis. We recently reported that PAHs down-regulated the liver X receptor (LXR) alpha-regulated genes via aryl hydrocarbon receptor (AHR) as one of the causes responsible for atherosclerosis induced by PAHs. Thus, the aim of this study was to clarify the role of CYP1A1 in the suppression of LXR-mediated signal transductions by 3-methlychoranthrene (MC), one of the PAHs. We found that LXR-mediated transactivation was inhibited by the PAH, but not by halogenated aromatic hydrocarbon, which is scarcely metabolized by CYP1A1. The repression of LXR-mediated signal transductions by MC was restored by co-treatment of HepG2 cells with a CYP1A1 inhibitor, alpha-naphthoflavone, and by the transfection of short interference RNA for CYP1A1. Based on these lines of evidence, we propose that the metabolic activation of PAHs by CYP1A1, but not the activation of AHR by PAHs, is a direct mechanism for atherosclerosis via the suppression of LXR-mediated signal transductions.
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PMID:CYP1A1-mediated mechanism for atherosclerosis induced by polycyclic aromatic hydrocarbons. 1620 79


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