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)

Cigarette smoking is a leading risk factor for atherosclerosis. Endothelial injury may be the initial event in this process. The carcinogenic metabolites of the polycyclic aromatic hydrocarbons found in cigarette smoke tars could cause this injury. We tested this model by examining the effect of 3-methylcholanthrene administration on aortic polycyclic aromatic hydrocarbon metabolism. Immunoblotting with a monoclonal antibody (mAb 1-7-1) specific for cytochromes CYPIA1 and CYPIA2 showed that aortic microsomes from treated, but not from control, animals contained CYPIA1; the CYPIA1 was primarily in the endothelium. Aortic microsomes from induced animals metabolized benzo[a]pyrene (BaP) to the 7R,8S,9,10-tetrahydrotetrol-, 7,8-dihydrodiol-, 1,6 quinone-, 3,6 quinone-, 6,12 quinone-, 3-hydroxy-, and 9-hydroxy-BaP. mAb 1-7-1 inhibited the formation of the tetrahydrotetrol, the dihydrodiol-BaP, and the 3-hydroxy-BaP but did not inhibit the quinones or the 9-hydroxy-BaP. Arachidonic acid did not affect metabolism. These data suggest that the aortas of induced animals metabolize the BaP in cigarette smoke to carcinogenic and toxic products and that this metabolism may initiate vessel injury and lead to the accelerated atherosclerosis seen in cigarette smokers.
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PMID:Induction of cytochrome CYPIA1 and formation of toxic metabolites of benzo[a]pyrene by rat aorta: a possible role in atherogenesis. 820 97

Glutathione transferases play an important role in the detoxification of many different endogeneous and exogenous compounds such as metabolites of polycyclic aromatic hydrocarbons (PAH) of cigarette tar. There is evidence that PAH may be atherogenic. The glutathione transferase activity towards trans-stilbene oxide (GST-tSBO) can be separated in blood in GST-positive and GST-negative phenotypes. We have previously suggested that the GST-negative phenotype may be associated with a higher morbidity in intermittent claudication among middle aged smokers. In the present study, GST-tSBO could easily be measured in human, rabbit and bovine arterial smooth muscle cells (SMC) in culture. The level of GST-tSBO was higher in rabbit than in bovine SMC. It was stable in bovine SMC during 5 cell passages and it could be induced twofold by long-time incubation with dimethylsulfoxide-soluble particulate matter from cigarette smoke or 3,4-benzo(a)pyrene. There was a positive correlation between the level of GST-tSBO in blood and in "healthy" arterial and venous tissue from individuals operated with coronary bypass. The enzyme levels in arterial tissue were lower than in venous tissue. GST-tSBO in atherosclerotic segments of human arteries was lower than in "healthy" segments from the same artery. These findings suggest that the arterial wall may have a low defense against toxic compounds that may decrease further as atherosclerosis proceeds. It is concluded that SMC are suitable for the study of the effects of PAH in relation to GST-tSBO and that the enzyme activity in blood will reflect the individual GST-tSBO phenotype also in vascular tissues.
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PMID:Glutathione transferase activity in human vessels and in cultured arterial smooth muscle cells. 820 12

Benzo(a)pyrene (BaP), a major environmental pollutant and component of cigarette smoke, is both carcinogenic and atherogenic in experimental models. We investigated the effect of long-term administration of BaP on atherogenesis in both atherosclerosis-susceptible White Carneau (WC) and atherosclerosis-resistant Show Racer (SR) pigeons. The number and size of arterial lesions in the brachiocephalic arteries in WC and SR females but not males were significantly enhanced after long-term dosing with BaP. Metabolic activation appears to be required for BaP atherogenicity, since benzo(e)pyrene (BeP), a noncarcinogenic analogue of BaP, did not enhance lesion development. Studies with 3H-BaP revealed no significant differences between male and female or between WC and SR pigeons in the arterial distribution of BaP and/or its metabolites. There were no consistent differences in blood pressure or plasma cholesterol levels between breeds or sexes. However, chronic administration of BaP did result in complete infertility in female birds, concomitant with grossly visible changes in ovarian appearance. These results clearly show that long-term dosing with BaP alters ovarian structure and function in treated birds, at the same time aggravating the development of arterial lesions. Thus, BaP-induced atherogenicity in female pigeons may be a consequence of an alteration in estrogen production or of antiestrogenic properties of BaP at the level of the arterial wall and may serve as a highly useful animal model to examine the well-known rapid development of atherosclerosis in postmenopausal women.
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PMID:Benzo(a)pyrene enhances atherosclerosis in White Carneau and Show Racer pigeons. 824 Oct 91

DNA adducts are biomarkers evaluating the biologically effective dose of carcinogens, which reflects, more realistically than the external exposure dose, an enhanced risk of developing cancer. Likewise, inhibition of DNA adduct formation can be assumed as an indicator of decreased risk. Molecular dosimetry techniques can be exploited in anticarcinogenicity studies in animal models as well as in Phase II clinical chemoprevention trials. We have extensively used these end points in animal studies using individual carcinogens and complex mixtures. As assessed by 32P-postlabelling, DNA adducts were formed in the liver of rats fed a diet supplemented with 2-acetylaminofluorene. DNA adducts were detected by synchronous fluorescence spectrophotometry (SFS) in rat liver, lung, heart and testis following intratracheal (l.t) instillations of benzo[a]pyrene. The whole-body exposure of rats to mainstream cigarette smoke resulted in the appearance of DNA adducts in lung, heart, aorta and kidney, whereas adducts were not detected by SFS in liver, brain, oesophagus and testis. Moreover, typical diagonal radioactive zones and multiple DNA adducts were revealed by 32P-postlabelling in the tracheal epithelium, nasal mucosa, aorta and testis of smoke-exposed rats. Formation of adducts to lung DNA, as assessed by both 32P-postlabelling and SFS, also occurred in rats receiving i.t. instillations of air particulate extracts from polluted urban and rural areas. The oral administration of the thiol N-acetylcysteine (NAC) significantly inhibited the formation of DNA adducts in all organs of the rats exposed to the aforementioned carcinogens, which correlated with the parallel inhibition of biochemical, cytogenetic and histopathological alterations as well as with inhibition of preneoplastic and neoplastic lesions in rodents. Our working hypothesis is that DNA adducts in trachea/lung, heart and aorta may be associated with lung cancer, cardiomyopathies and atherosclerosis, respectively. DNA adducts were consistently detectable in the DNA of smooth muscle cells from abdominal aorta specimens taken at surgery from atherosclerotic patients. Even broader are the consequences of mitochondrial (mt) DNA impairment, which has been associated with aging, cancer, and other degenerative diseases. Our data show that adduct levels are consistently higher in mtDNA than in the nuclear DNA in different organs of rats exposed either to benzo[a]pyrene, 2-acetylaminofluorene or cigarette smoke. NAC significantly decreased the formation of adducts to mtDNA when administered with drinking-water. Inhibition of adducts to nuclear DNA is one of the end points evaluated in ongoing Phase II chemoprevention trials in high-risk individuals.
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PMID:Adducts to nuclear DNA and mitochondrial DNA as biomarkers in chemoprevention. 892 39

The effect of the apolipoprotein C-II/C-III1 ratio on the capacity of purified bovine milk lipoprotein lipase to hydrolyse triglycerides was measured in a controlled model of pyrene-labeled nonanoyltriglycerides (1-2 ditetradecyl 3-pyrene nonanoyl glyceride) monolayer vesicles. Monolayer was composed of triglycerides, a non-hydrolysable phospholipid ether and cholesterol, a model system where the quality of the interface can be controlled. LPL released fatty acids from pyrene-triglycerides which were transferred from the lipoprotein structure to albumin. This transfer induces a decrease in the excimer production and in the excimer fluorescence intensity. Apolipoprotein C-II and C-III0 and C-III1 were purified from apolipoprotein VLDL. The 2 fragments, C-III1 A (peptide 1-40) and C-III1 B (peptide 41-79), were obtained after thrombin cleavage. Apolipoproteins C-III0 and C-III1 had a similar inhibitory effect on LPL. Inhibition with apo C-III0 or apo C-III1 was 85% of full LPL activity without inhibitor: Apo C-III1 B inhibited 62% of basal activity. It was 27% less effective than apo C-III1. Fragment C-III1 A did not inhibit LPL. The effect of change in both apo C-II (0-0.6 microM) and apo C-III1 (0-1.0 microM) on triglyceride hydrolysis shows the importance of the apo C-II/C-III1 ratio for the release of free fatty acids from triglycerides by LPL. The activating effect of apo C-II in the absence of the apo C-III inhibitor was maximal at 0.06 microM. No further activation was obtained between 0.06 and 0.30 microM. Higher concentrations decreased LPL activity. Apo C-III1 (0.1 microM) decreased the maximum activation by apo C-II from 0.0196 to 0.063 nmol/min/nmol LPL. Higher concentrations of apo C-III1 (0.1-0.5 microM) required higher apo C-II concentrations (0.30 microM instead of 0.06 microM) for maximal activation than when apo C-III1 was absent. The activity of the enzyme without apo C-II was decreased by 65% by 0.12 microM apo C-III1. Increasing the apo C-II/apo C-III1 ratio from 0.1 to 1, increased the activation of the enzyme by a given apo C-II concentration. Moreover, for a given apo C-II/C-III1 ratio, the LPL activation increased with the apo C-II concentration (between 0 and 0.010 microM), until a plateau was reached. This is important, as the change in the C-II/C-III1 ratio is not the only factor affecting LPL activity, and inhibition by apo C-III1 also depends on the overall quantity of apolipoproteins. Extrapolation of these results suggests that hyperlipoproteinemia seems to be more likely due to overproduction of VLDL, than to a decrease in lipoprotein lipase activity.
Atherosclerosis 1996 Dec 20
PMID:Effect of the apolipoprotein C-II/C-III1 ratio on the capacity of purified milk lipoprotein lipase to hydrolyse triglycerides in monolayer vesicles. 912 10

As reviewed in the Part I companion manuscript by Basavaraju and Jones (Arch Environ Contam Toxicol), atherosclerosis and carcinogenesis may share some common mechanisms of toxicological action. On that hypothesis, standardized test data taken from the Registry of Toxic Effects of Chemical Substances (RTECS) were used to compute relative potency factors for chemical compounds associated with increased risk of atherosclerosis to humans. Potencies of the different compounds were computed relative to each of six reference compounds comprised of benzo(a)pyrene, nicotine, cisplatin, adriamycin, estrogen, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Reference-specific potencies were all converted to a common numerical scale adjusted to unit potency for B(a)P. Because the list of compounds contained several antibiotics, amino acids, hormones, chemotherapeutic agents, polynuclear aromatics, alkaloids, metals, and vitamins, the standardized estimates of potency varied significantly depending on which of the six reference compounds are considered as standards of comparison. For the n - 1 other substances. Estimates of relative potency, risk coefficients, and generalized risk equations are estimated for cigarette smoke condensate, dietary cholesterol, ethanol, and carbon disulfide. From data on atherosclerosis as a result of cigarette smoking, a tentative risk was estimated as Increased Relative Risk = S (mg/kg-day)-1 x dose (mg/kg-day) x RP, where the dose is chronic intake per kilogram of body weight per day, RP is the potency of the compound of interest relative to that of benzo(a)pyrene, and S is 0.83, 0.25, 0.20, or 13 depending on whether cigarette smoke, cholesterol, ethanol, or carbon disulfide epidemiological data were used as a standard of comparison.
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PMID:Atherosclerotic risks from chemicals: part II. A RASH analysis of in vitro and in vivo bioassay data to evaluate 45 potentially hazardous compounds. 960 35

The displacement of apolipoprotein (apo) A-I by apo A-II is a major event in the remodeling of high density lipoproteins (HDL). In the present study, we investigated the displacement of apo A-I both from native and reconstituted HDL (rHDL) by either apo A-II or by the C-terminal helical peptide (i.e. residues 53-70). We studied the remodeling process of the original particles, the changes in size and composition and in their lecithin:cholesterol acyltransferase (LCAT) activating properties. Using gel filtration, we show that, at low apo A-II/AI ratios, the initial lipid apolipoprotein complex containing 2 mol apo A-I is remodeled into a mixed complex containing apo A-I and apo A-II, involving the displacement of one apo A-I by apo A-II. Upon addition of a larger amount of apo A-II, the rHDL particles become more heterogeneous and of larger size. Immunoblotting of the particles separated by non denaturing gradient gel electrophoresis shows that most of the apo A-I remains associated with the largest particles. The LCAT activation properties of the remodeled complexes decrease upon addition of either apo A-II or its C-terminal helix. This decrease is more pronounced when rHDL are incubated with the apo A-II C-terminal helix than with native apo A-II, as VmaX decreases from 28 to 16 and 7 nmol cholesteryl ester/ml per h respectively, whereas Km remains unchanged. The displacement of apo A-I observed with rHDL also occurred with native HDL particles as demonstrated by two-dimensional gel electrophoresis, using pyrene-phospholipid labeled HDL. Displacement of apo A-I generates pre-beta1 migrating particles containing apo A-I and phospholipids. We therefore propose that apo A-II has a dual effect on the role of HDL in reverse cholesterol transport: displacement of apo A-I from rHDL results in a negative control of the LCAT activity, while generation of pre-beta1 migrating particles enhances the formation of potential acceptors of cellular cholesterol.
Atherosclerosis 1998 Aug
PMID:Displacement of apo A-I from HDL by apo A-II or its C-terminal helix promotes the formation of pre-beta1 migrating particles and decreases LCAT activation. 971 42

The presence of cigarette smoking-related polycyclic aromatic hydrocarbon (PAH)-DNA adducts was investigated in human arterial tissue using an immunoperoxidase staining method with a monoclonal antibody that recognizes benzo(a)pyrene and structurally related PAH diol epoxide-DNA adducts. This is the first time that immunohistochemical methods for detection of PAH-DNA damage have been applied to human endothelial and smooth muscle cells of blood vessels. Internal mammary artery specimens from a total of 37 smokers and non-smokers were tested. Positive nuclear staining was observed in both endothelial and smooth muscle cells, with higher staining in the endothelium. The correlation between smoking status, available for 33 subjects, and detectable PAH-DNA adducts in endothelium did not reach statistical significance (odds ratio = 3.38, 95% confidence interval is 0.47-27.60) in this small series. While no causal role can be inferred from our results, they support the theory that endothelial injury caused by cigarette smoking and other environmental exposures may be an early event in the process of atherosclerosis.
Atherosclerosis 1998 Oct
PMID:Immunohistochemical detection of polycyclic aromatic hydrocarbon-DNA damage in human blood vessels of smokers and non-smokers. 986 75

Phosphatidylcholines (1-O-alcoxy-2-amino-2-desoxy-phosphocholines and 1-pyrene-labeled analogs) were synthesized and used to examine interactions with recombinant human PAF-acetylhydrolase (PAF-AH), an enzyme purified from plasma, and with macrophage-like U937 cells. Novel phosphatidylcholines containing a sn-2-carbamoylester group such as 1-O-hexadecyl-2-desoxy-2-amino-methylcarbamoyl-2-methyl-rac-glycer o-3-phosphocholine 11 were found to act as site-specific irreversible enzyme inhibitors with Ki-values up to 83 (K(irev)) and 177 (Ki(inact)) microm. The compounds exhibit only marginal inhibition of Ca2+-dependent phospholipases. Kinetic data show that phosphocholines carrying a terminal sn-1-pyrene moiety inhibit PAF-AH activity with an effectivity similar to analogs with an aliphatic chain. 1-O-Decyloxy-[10-(4-pyrenyl)-butoxy]-2-desoxy-2-amino-carbamoyl-me thyl-rac(-glycero-3-phosphocholine 13 could be used for enzyme labeling and to demonstrate an inhibitor-enzyme stoichiometry of 0.7:1. At 8 degrees C, the compound accumulated in the membranes of U937 cells, at 37 degrees C it was internalized into intracellular compartments. Structure activity studies in a mixed micelle assay indicated that the inhibition power of reversible and irreversible inhibitors increases along with the (sn)-1-chain length similar to the structure-dependent binding of ether phospholipids to the PAF-receptor. Unlike the situation at the (sn)-1-position, increasing chain length at the sn-2-position, or an alkyl branching of the glycerol backbone significantly reduced the inhibitory potency.
Atherosclerosis 1999 May
PMID:Novel reversible, irreversible and fluorescent inhibitors of platelet-activating factor acetylhydrolase as mechanistic probes. 1038 Dec 81

Polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P) present in tobacco smoke and tar, have been implicated in the development of atherosclerosis as well as cancer. Increased expression of cyclooxygenase-2 (COX-2) has been detected both in atherosclerotic lesions and in epithelial cancers. To determine whether polycyclic aromatic hydrocarbons might directly affect COX expression in vascular cells, we investigated the effects of B[a]P on COX-2 expression in human and rat arterial smooth muscle cells (SMC). Treatment with B[a]P increased levels of COX-2 protein and mRNA and enhanced prostaglandin synthesis. Nuclear runoff assays and transient transfections revealed increased COX-2 gene transcription after treatment with B[a]P. Experiments were done to define the signaling mechanism by which B[a]P induced COX-2. B[a]P caused a rapid increase in phosphorylation of extracellular signal-regulated kinase (ERK); pharmacologic inhibition of mitogen-activated protein kinase kinase blocked B[a]P-mediated induction of COX-2. Depletion of the intracellular antioxidant, glutathione, with buthionine sulfoximine significantly increased B[a]P-mediated induction of COX-2 while exposure to N-acetylcysteine, a precursor of glutathione, suppressed the induction of COX-2 by B[a]P. Several lines of evidence suggest that the induction of COX-2 by B[a]P is mediated, at least in part, by NF-kappaB. Treatment with B[a]P increased binding of NF-kappaB to DNA. Moreover, B[a]P-mediated stimulation of COX-2 promoter activity was blocked when a construct containing a mutagenized NF-kappaB site was used. Pharmacological inhibitors of NF-kappaB blocked the induction of COX-2 protein and the stimulation of COX-2 promoter activity by B[a]P. Taken together, these data are likely to be important for understanding the atherogenic effects of tobacco smoke.
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PMID:Benzo[a]pyrene induces the transcription of cyclooxygenase-2 in vascular smooth muscle cells. Evidence for the involvement of extracellular signal-regulated kinase and NF-kappaB. 1067 33


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