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)

Polycyclic aromatic hydrocarbons, cigarette smoke components that induce atherosclerosis in animals, require metabolic biotransformation to electrophilic intermediates to exhibit atherogenic effects. The formation of reactive metabolites depends on both rates of cytochrome P450-catalyzed oxidation and rates of detoxification through conjugation with glutathione. Thus, changes in the activity of glutathione S-transferase in vascular tissue could affect the risk of polycyclic aromatic hydrocarbon-induced atherogenesis. We compared the effects of several exogenous chemicals on levels of glutathione S-transferase in aorta and liver. Male Wistar rats were treated with 3-methylcholanthrene, a polycyclic aromatic hydrocarbon, phenobarbital and butylated hydroxytoluene, an antioxidant known to have anti-atherogenic properties. In control animals, glutathione S-transferase activity was about 20-fold greater in liver than in aorta. Subunit expression was tissue specific. GST-Yp, for example, was the most abundant subunit in aorta but was undetectable in liver. In contrast, GST-Ya was barely detectable in aorta but was abundant in liver. Each of the xenobiotics caused induction of glutathione S-transferase but the extent of induction was greater in liver than in aorta. Phenobarbital, for example, caused 300% induction in liver but only 70% induction in aorta. By western blot analysis, differences in amounts of enzyme subunits corresponded to changes in enzyme activity. Thus, exogenous chemicals differentially regulate levels of glutathione S-transferase in the aorta and liver.
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PMID:Differential induction of glutathione S-transferase in rat aorta versus liver. 820 8

The objective of the present study was to investigate the expression of major xenobiotic-metabolising cytochrome P450 proteins, and of other enzyme systems, in hepatic and extrahepatic tissues of rabbits rendered atherosclerotic by the dietary administration of 1% cholesterol diets for 8 weeks. Individual cytochrome P450 proteins were monitored using diagnostic substrates and immunologically in Western blot analysis. The activity of all hepatic isoforms studied was depressed in the atherosclerotic animals; when, however, apoprotein levels were determined immunologically, no major differences were evident between the control and the atherosclerotic rabbits. In vitro studies indicated that neither cholesterol nor palm oil inhibited cytochrome P450 activity. The effects of cholesterol treatment leading to atherosclerosis on kidney, heart and lung cytochrome P450 activities were isoform- and tissue-specific; no change was evident in the heart activities, but in the lung and kidney cytochrome P450 activities were clearly modulated by the treatment with cholesterol. Apoprotein levels did not always parallel the changes in activities. Western blot analysis of aortic cytochromes P450 revealed that administration of cholesterol-rich diets enhanced CYP2B and CYP3A apoprotein levels. Cholesterol feeding to rabbits gave rise to a marked decrease in hepatic glutathione S-transferase activity but did not influence glutathione reductase or total glutathione levels. The same treatment had no effect on catalase, glutathione peroxidase and superoxide dismutase. It is concluded that treatment of rabbits with cholesterol-rich diets leading to atherosclerosis gives rise to profound changes in the expression of cytochrome P450 proteins in the liver and other tissues; possible mechanisms are discussed.
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PMID:Marked inhibition of hepatic cytochrome P450 activity in cholesterol-induced atherosclerosis in rabbits. 967 66

Interleukin-6 (IL-6) is a pleiotropic cytokine, whose plasma levels are elevated in inflammatory diseases such as atherosclerosis. We have previously reported that peroxisome proliferator-activated receptor alpha (PPARalpha) ligands (fibrates) lower elevated plasma concentrations of IL-6 in patients with atherosclerosis and inhibit IL-1-stimulated IL-6 secretion by human aortic smooth muscle cells (SMC). Here, we show that aortic explants isolated from PPARalpha-null mice display an exacerbated response to inflammatory stimuli, such as lipopolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPARalpha wild-type, but not of PPARalpha-null mice, demonstrating a role for PPARalpha in this fibrate action. In human aortic SMC, fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPARalpha represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPARalpha and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPARalpha-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPARalpha, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPARalpha-mediated transcriptional repression of p65 and c-Jun. Finally, glutathione S-transferase pull-down experiments demonstrate that PPARalpha physically interacts with c-Jun, p65, and CBP. Altogether these data indicate that fibrates inhibit the vascular inflammatory response via PPARalpha by interfering with the NF-kappaB and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.
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PMID:Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. 1054 37

Polysaccharide krestin (PSK) is a protein-bound polysaccharide extracted from the sporophore Coriolus versicolor. Previously, we found that PSK could reduce the oxidative injury that oxidised low-density lipoprotein (Ox-LDL) produced in monocytes/macrophages, and therefore have some pro-phylactic or therapeutic effect on atherosclerosis. Glutathione peroxidases, including selenium-dependent glutathione peroxidase (SeGPx) and non-selenium-dependent glutathione peroxidase (non-SeGPx, also called glutathione S-transferase [GST]), play an important role in the defence against oxidative injury. In order to find out if the effects of PSK were associated with antioxidant enzymes, we investigated its effect on glutathione peroxidase activity and messenger RNA (mRNA) expression in mouse peritoneal macrophages. Results showed that PSK enhanced SeGPx and non-SeGPx activity, and increased SeGPx and GST-P (pi class GST) mRNA in mouse peritoneal macrophages. In addition, the induction by PSK of the two glutathione peroxidases could be blocked by cycloheximide (30 micrograms/mL), but 5 micrograms/mL actinomycin D and 50 micrograms/mL acetovanilone (a superoxide inhibitor) had no effect. We conclude that PSK improved glutathione peroxidase activity through transcriptional induction of mRNA expression.
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PMID:Effect of polysaccharide krestin on glutathione peroxidase gene expression in mouse peritoneal macrophages. 1091 87

Angiotensin (A) II plays a critical role in vascular remodeling, and its action is mediated by type 1 AII receptor (AT1R). Recently, 15-deoxy-(Delta)(12,14)-prostaglandin J(2) and thiazolidinediones have been shown to be ligands for peroxisome proliferator-activated receptor (PPAR)-gamma and activate PPAR-gamma. In the present work, we have studied the effect of PPAR-gamma on AT1R expression in rat vascular smooth muscle cells (VSMCs). We observed that: 1) endogenous AT1R expression was significantly decreased by PPAR-gamma ligands both at messenger RNA and protein levels, whereas AT1R messenger RNA stability was not affected; 2) AII-induced increase of (3)H-thymidine incorporation into VSMCs was inhibited by PPAR-gamma ligands; 3) rat AT1R gene promoter activity was significantly suppressed by PPAR-gamma ligands, and PPAR-gamma overexpression further suppressed the promoter activity; 4) transcriptional analyses using AT1R gene promoter mutants revealed that a GC-box-related sequence within the -58/-34 region of the AT1R gene promoter was responsible for the suppression; 5) Sp1 overexpression stimulated AT1R gene transcription via the GC-box-related sequence, which was inhibited by additional PPAR-gamma overexpression; 6) electrophoretic mobility shift assay suggested that Sp1 could bind to the GC-box-related sequence whereas PPAR-gamma could not; 7) antibody supershift experiments using VSMC nuclear extracts revealed that protein-DNA complexes formed on the GC-box-related sequence, which were decreased by PPAR-gamma coincubation, were mostly composed of Sp1; and 8) glutathione S-transferase pull-down assay revealed a direct interaction between PPAR-gamma and Sp1. Taken together, it is suggested that activated PPAR-gamma suppresses AT1R gene at a transcriptional level by inhibiting Sp1 via a protein-protein interaction. PPAR-gamma ligands, thus, may inhibit AII-induced cell growth and hypertrophy in VSMCs by AT1R expression suppression and possibly be beneficial for treatment of diabetic patients with hypertension and atherosclerosis.
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PMID:Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells. 1141 35

We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase mu-1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P=0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus -0.002 mm, P=0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P=0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST mu-1 develop progression of atherosclerosis at an increased rate.
Atherosclerosis 2001 Sep
PMID:Effect of glutathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers. 1150 Jan 95

Thromboxane (TX) A(2) exerts contraction and proliferation of vascular smooth muscle cells (VSMCs) via its specific membrane TX receptor (TXR), possibly leading to the progression of atherosclerosis. A nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, has recently been reported to be expressed in VSMCs. Here we examined a role of PPAR-gamma in TXR gene expression in VSMCs. PPAR-gamma ligands 15-deoxy-Delta(12,14)-prostaglandin J(2) and troglitazone reduced TXR mRNA expression levels as well as cell growth as assessed by [(3)H]thymidine incorporation. Transcriptional activity of the TXR gene promoter was suppressed with PPAR-gamma ligands, and the suppression was augmented further by PPAR-gamma overexpression. By deletion and mutation analyses, the transcription suppression was shown to be the result of a -22/-7 GC box-related sequence (upstream of transcription start site). Electrophoretic mobility shift assays also showed that the sequence was bound by Sp1 but not by PPAR-gamma, and the formation of a Sp1 small middle dotDNA complex was inhibited either by coincubation with PPAR-gamma or PPAR-gamma ligand treatment of VSMCs. Moreover, glutathione S-transferase pull-down assays demonstrated a direct interaction between PPAR-gamma and Sp1. In conclusion, PPAR-gamma suppresses TXR gene transcription via an interaction with Sp1. PPAR-gamma may possibly have an antiatherosclerotic action by inhibiting TXR gene expression in VSMCs.
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PMID:Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Sp1 in vascular smooth muscle cells. 1177 1

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an enzyme involved in cellular cholesterol homeostasis and atherosclerosis. ACAT1 is an allosteric enzyme responding to its substrate cholesterol in a sigmoidal manner. It is a homotetrameric protein that spans the membrane multiple times, with its N-terminal 131 hydrophilic amino acids residing at the cytoplasmic side of the endoplasmic reticulum. This region contains two closely linked putative alpha-helices. Our current studies show that this region contains a dimer-forming motif. Adding this motif to the bacterial glutathione S-transferase (GST) converted the homodimeric GST to a tetrameric fusion protein. Conversely, deleting this motif from the full-length ACAT1 converted the enzyme from a homotetramer to a homodimer. The dimeric ACAT1 remains enzymatically active. Its biochemical characteristics, including the sigmoidal response to cholesterol, the IC(50) value toward a specific ACAT inhibitor, and sensitivity toward heat inactivation, are essentially unaltered. On the other hand, the dimeric ACAT1 exhibits a 5-10-fold increase in the V(max) of the overall reaction and a 2.2-fold increase in the K(m) for oleoyl-coenzyme. Thus, deleting the dimer-forming motif near the N-terminus changes ACAT1 from its tetrameric form to a dimeric form and increases its catalytic efficiency.
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PMID:Role of the N-terminal hydrophilic domain of acyl-coenzyme A:cholesterol acyltransferase 1 on the enzyme's quaternary structure and catalytic efficiency. 1188 94

Oxidative stress has been implicated in the development of atherosclerotic lesions. We evaluated the relationship between extent of atherosclerotic lesion formation and vascular expression of pro- and antioxidant enzymes in apoE-deficient mice. On normal chow, these mice showed elevated serum cholesterol levels (7.5- to 9.5-fold), and age-dependent, spontaneous development of all stages of atherosclerotic lesions, starting at the age of 12 weeks. RNA was extracted from the aortic arch and descending aorta, and mRNA expression of pro- and antioxidant enzymes was measured with real-time PCR. Local infiltration of monocytes/macrophages, reflected by increased vascular expression of CD68 mRNA (>10-fold), indicated that the arch was more susceptible than the descending aorta. The expression of catalase-1 and various isoforms of superoxide dismutase, glutathione peroxidase, and glutathione S-transferase alpha was significantly increased in the aortic arch, but not in the descending aorta, in the period preceding lesion formation (age 6 to 12 weeks). These expression levels were 1.5 to 5 times higher than in age-matched wild-type animals. Remarkably, there was an inverse relationship between extent of lesion formation and the mRNA levels of antioxidant enzymes, most of which started to decline after 12 weeks, as lesions developed. In contrast, inducible nitric oxide synthase expression increased 4-fold in the aortic arch over the course of the disease. Our results suggest that the arterial wall responds to increased serum levels of atherogenic lipoproteins by stimulating expression of antioxidant enzymes. The observed co-ordinate decline in expression of many of these protective systems may greatly accelerate the development of atherosclerosis.
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PMID:Aorta of ApoE-deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes. 1290 62

Prostaglandin (PG) D synthase (PGDS) catalyzes the isomerization of PGH(2) to PGD(2), which acts as an endogenous somnogen and an allergic mediator. There are two distinct types of PGDS: one is lipocalin-type PGDS (L-PGDS) localized in the central nervous system, male genitals, and heart; and the other is hematopoietic PGDS (H-PGDS) in mast cells and Th2 lymphocytes. L-PGDS is the same as beta-trace, a major protein in human cerebrospinal fluid, and is also secreted into the seminal plasma and plasma. The L-PGDS concentration in various body fluids is useful as a marker for various diseases such as renal failure and coronary atherosclerosis. H-PGDS is a cytosolic enzyme and is a member of the Sigma class of glutathione S-transferase. We determined the X-ray crystallographic structures of H-PGDS and L-PGDS. We also generated the gene-knockout (KO) mice and the human enzyme-overexpressing transgenic mice for each PGDS. L-PGDS-KO mice lacked PGE(2)-induced tactile allodynia and rebound of non-rapid eye movement sleep after sleep deprivation. Human L-PGDS-overexpressing transgenic mice showed an increase in non-rapid eye movement sleep due to accumulation of PGD(2) in the brain after tail clipping. H-PGDS-KO mice showed an allergic reaction weaker than that of the wild-type mice.
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PMID:[Functional analyses of lipocalin-type and hematopoietic prostaglandin D synthases]. 1469 53


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