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)

There is accumulating evidence for the importance of small, dense low-density lipoprotein (LDL), the defining feature of the atherogenic lipoprotein phenotype, as a risk factor for coronary heart disease. Although both family studies and twin studies have demonstrated genetic influences on this phenotype, the specific gene(s) involved remain to be identified. The purpose of this study was to determine whether there was evidence for genetic linkage between small, dense LDL (LDL subclass phenotype B), as determined by gradient gel electrophoresis, and selected candidate genes known to be involved in lipid metabolism. The linkage analyses were based on a sample of 19 families, including 142 individual family members, using a lod score linkage analysis approach. Nine candidate genes were examined, including loci for manganese superoxide dismutase (Mn SOD2), apolipoproteins CIII, AII, and apo CII, lipoprotein lipase, hepatic lipase, microsomal triglyceride transport protein, the insulin receptor and the LDL receptor. The analyses did not provide significant evidence for genetic linkage between markers for any of these genes and LDL subclass phenotype B, nor did it confirm previous reports of linkage between the LDL receptor gene and LDL subclass phenotype B. Using three closely linked markers for the Mn SOD2 locus excluded close linkage between this candidate gene region and LDL subclass phenotype B. These findings demonstrate the complexity of genetically mapping risk factor phenotypes, and emphasize the necessity of identifying new genetic loci, other than known candidate genes, involved in susceptibility to atherosclerosis.
Atherosclerosis 1999 Jan
PMID:Linkage analysis of candidate genes and the small, dense low-density lipoprotein phenotype. 992 May 8

We have investigated the effects of cholesterol and omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexenoic acid (DHA) on Na, K-ATPase activity in human endothelial cells (HUVEC). Cultured HUVEC were incubated for 18 h with pure egg phosphatidylcholine (PC), or cholesterol-enriched liposomes (4 mg PC/ml). EPA and DHA alpha-tocopherol-acetate were emulsified with PC and incubated with HUVEC (10 mM). Na, K-ATPase and 5'-nucleotidase activities were determined using the coupled assay method on microsomal fractions obtained from cultured cells using non treated cells as control. Cholesterol enrichment significantly reduced both Na, K-ATPase and 5'-nucleotidase activities by a similar level (- 40%), whereas pure phospholipid liposomes inhibited this activity only by 22%. The dose-response curves of Na, K-ATPase activity were all biphasic assuming the presence of two independent sites exhibiting different affinities for ouabain of nM and microM respectively. The cholesterol induced inhibitory effect was greater for low affinity sites (-54%) as compared to that of the high affinity sites (-24%) whereas omega-3 fatty acids reduced the activity of both sites by 22%. Short term effects of EPA and DHA on Na, K-ATPase activity were determined by incubating microsomal fractions from untreated cells with various concentrations of free fatty acids (from 1 to 200 microM) for 20 min. Both EPA and DHA significantly reduced Na, K-ATPase activity but inhibition by EPA seems to be more effective than DHA. These results suggest that cholesterol and omega-3 fatty acids reduce Na, K-ATPase activity in HUVEC.
Atherosclerosis 1999 Feb
PMID:Cholesterol and omega-3 fatty acids inhibit Na, K-ATPase activity in human endothelial cells. 1003 Mar 84

Low density lipoprotein (LDL) oxidation is a major contributor to foam cell formation during early atherogenesis. Several oxygenases have been implicated in the process of LDL oxidation in the arterial wall, where the environment is relatively low in antioxidants, but the exact mechanism for LDL oxidation in vivo is not known. In the present study we sought to determine the ability of cytochrome P450 2E1 (P450 2E1) and other P450s, located in the liver and in other tissues, to oxidize LDL. Upon incubation of LDL (0.1 mg of protein/ml) with purified, reconstituted rabbit P450 2E1 in the presence of NADPH and the NADPH-cytochrome P450 reductase, time- and P450 2E1 concentration-dependent LDL oxidation was observed, as analyzed by determining the formation of peroxides, thiobarbituric acid reactive substances (TBARS), and conjugated dienes. Within 1 h of initiating the reaction, almost maximal oxidation was observed. NADPH, and active P450 2E1 enzyme were required for LDL oxidation to occur. The rate of P450 2E1-induced LDL oxidation was also dependent on the lipoprotein concentration. P450 2E1 could also oxidize pure phospholipids and cholesteryl ester, the major lipids in LDL. In the presence of catalase or superoxide dismutase (SOD), LDL oxidation was completely blocked, suggesting that hydrogen peroxide and superoxide are involved in P450 2E1-induced LDL oxidation. The ability of P450 2E1 to oxidize LDL was not unique to this enzyme, and could be observed with some other purified, cytochromes P450 in the reconstituted system such as rat P450 2B1 and human P450 3A4. Finally, microsomal membranes obtained from rats that were induced to express high levels of P450s 2B1, 2E1, and 1A1/2 were able to oxidize LDL, whereas little oxidation was seen with microsomes that were induced to express 3A2. We thus conclude that LDL can be oxidized by some cytochrome P450s and, as some of these enzymes are present in liver and in arterial wall, they may have a physio/pathological relevance to LDL oxidation and atherogenesis.
Atherosclerosis 1999 Apr
PMID:Microsomal cytochromes P450 catalyze the oxidation of low density lipoprotein. 1021 53

Male Hartley guinea pigs were fed a hypercholesterolemic diet rich in lauric and myristic acids with 0, 10, or 20 mg/kg of simvastatin or atorvastatin for 21 days. Atorvastatin and simvastatin resulted in a lowering of plasma low-density lipoprotein (LDL) cholesterol in a dose-dependent manner by an average of 48 and 61% with 10 and 20 mg/kg, respectively. Both statins were equally effective in lowering plasma LDL cholesterol and apolipoprotein B (apo-B) levels. Atorvastatin and simvastatin treatments yielded LDL particles that differed in composition from the control. Due to the relevance of LDL oxidation and cholesteryl ester transfer in plasma to the progression of atherosclerosis, these parameters were analyzed after statin treatment. Atorvastatin and simvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% as determined by the formation of thiobarbituric acid reactive substances. An 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins was observed after simvastatin and atorvastatin treatment. In addition, statin effects on plasma LDL transport were studied. Simvastatin- and atorvastatin-treated guinea pigs exhibited 125 and 175% faster LDL fractional catabolic rates, respectively, compared with control animals. No change in LDL apo-B flux was induced by either treatment; however, LDL apo-B pool size was reduced after statin treatment. Hepatic microsomal free cholesterol was lower in the atorvastatin and simvastatin groups. However, only atorvastatin treatment resulted in an 80% decrease of acyl-CoA:cholesterol acyltransferase activity (P < 0.001). In summary, atorvastatin and simvastatin had similar LDL cholesterol lowering properties, but these drugs modified LDL transport and hepatic cholesterol metabolism differently.
 ...
PMID:Hypocholesterolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the guinea pig: atorvastatin versus simvastatin. 1048 79

Mammalian sterol regulatory enzymes are integral membrane proteins of the endoplasmic reticulum. They play a critical role in liver cholesterol homeostasis and the maintenance of overall cholesterol balance in different species. Because lipid peroxidation has been implicated in hepatic dysfunction and atherosclerosis, we hypothesized that its occurrence could alter the composition and properties of the bilayer lipid environment, and thereby affect the functions of these membrane proteins. Preincubation of rat liver microsomes with iron (Fe)/ascorbate (50 microM/200 microM), known to induce peroxidation, resulted in a significant inhibition of (i) the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase (46%, p < .01), (ii) the crucial enzyme controlling the conversion of cholesterol in bile acids, cholesterol 7alpha-hydroxylase (48%, p < .001), and (iii) the central enzyme for cholesterol esterification: Acyl-CoA:cholesterol acyltransferase (ACAT, 80%, p < .0001). The disturbances of these key enzymes took place concomitantly with the high production of malondialdehyde (350%, p < .007) and the loss of polyunsaturated fatty acids (36.19 +/- 1.06% vs. 44.24 +/- 0.41 in controls, p < .0008). While alpha-tocopherol simultaneously neutralized lipid peroxidation, preserved microsomal fatty acid status, and restored ACAT activity, it was not effective in preventing Fe/ascorbate-induced inactivation of both HMG-CoA reductase (44%, p < .01) and cholesterol 7alpha-hydroxylase (71%, p < .0001). These results indicate that Fe/ascorbate alters the activity of the rate-determining steps in liver cholesterol metabolism, either directly or via lipid peroxidation, capable of modifying their membrane environment. The present data also suggest that the three regulatory enzymes respond differently when exposed to Fe/ascorbate or antioxidants, which may be due to dissimilar mechanisms.
 ...
PMID:Modulation of endoplasmic reticulum-bound cholesterol regulatory enzymes by iron/ascorbate-mediated lipid peroxidation. 1065 90

Heme oxygenase-1 (HO-1) is a microsomal enzyme involved in the degradation of heme, resulting in the generation of biliverdin, iron, and carbon monoxide. Recent attention has focused on the biologic effects of product(s) of this enzymatic reaction that have important antioxidant, anti-inflammatory, and cytoprotective functions. Induction of HO-1 occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli, including heme, hydrogen peroxide, cytokines, growth factors, heavy metals, nitric oxide, and oxidized LDL. HO-1 has been implicated in several clinically relevant disease states, including transplant rejection, hypertension, acute renal injury, atherosclerosis, and others. Previous studies indicate a protective role for HO-1 in heme and non-heme-mediated models of acute renal injury using chemical inducers and inhibitors of HO-1. Studies in HO-1 knockout mice further corroborate these observations, highlighting the important role of HO-1 in the pathophysiology of acute renal injury. Expression of HO-1 has been linked to prolonged xenograft survival and is important in transplant rejection as well. More recently, the first known case of human HO-1 deficiency was reported with several phenotypical similarities to the mouse HO-1 knockout. The role of HO-1 has extended far beyond its initial description as an enzyme involved in heme degradation to being an important mediator in modulating adaptive and protective responses not only in renal injury, but in other organ systems as well.
 ...
PMID:Renal response to tissue injury: lessons from heme oxygenase-1 GeneAblation and expression. 1077 Sep 77

We aimed to determine the effects of carbamazepine, which induces liver microsomal enzymes, and valproic acid on the serum lipids and liver function test results in epileptic children. Thirty-eight epileptic children (18 males, 20 females, mean age 8.6 +/- 3.9 years) were evaluated for serum lipids and liver function test results at the onset and the second and sixth months of antiepileptic therapy. The results of the children receiving carbamazepine (n = 31) and valproic acid (n = 7) were compared. In addition, the values obtained at different periods of treatment were compared within each group. The differences in the serum lipid levels and liver function test results of the children in the carbamazepine group and the valproic acid group were not statistically significant throughout the study. However, the total cholesterol, low-density lipoprotein, total cholesterol/high-density lipoprotein, and gamma glutamyl transferase levels were significantly increased in the carbamazepine group during treatment (P < 0.05) but not in the valproic acid group. Carbamazepine treatment alters the serum lipid profile of the children in such a way that it facilitates the development of atherosclerosis. Valproic acid does not alter the levels of the serum lipids.
 ...
PMID:Carbamazepine and valproic acid: effects on the serum lipids and liver functions in children. 1102 Jun 39

Lifibrol (4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) is a new hypocholesterolemic compound; it effectively lowers low density lipoprotein (LDL) cholesterol. We studied the effects of lifibrol on the cholesterol metabolism of cultured cells. In the hepatoma cell line HepG2, Lifibrol decreased the formation of sterols from [14C]-acetic acid by approximately 25%. Similar to lovastatin, lifibrol had no effect on the synthesis of sterols from [14C]-mevalonic acid. Lifibrol did not inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Instead, cholesterol synthesis inhibition by lifibrol was entirely accounted for by competitive inhibition of HMG-CoA synthase. Lifibrol enhanced the cellular binding, uptake, and degradation of LDL in cultured cells in a dose dependent fashion. The stimulation of LDL receptors was significantly stronger than expected from the effect of lifibrol on sterol synthesis. In parallel, lifibrol increased the amount of immunologically detectable receptor protein. Stimulation of LDL receptor mediated endocytosis was observed both in the presence and in the absence of cholesterol-containing lipoproteins. In the absence of an extracellular source of cholesterol, both lifibrol and lovastatin induced microsomal HMG-CoA reductase. Co-incubation with LDL was sufficient to suppress the lifibrol mediated increase in reductase activity, indicating that lifibrol does not affect the production of the non-sterol derivative(s) which are thought to regulate HMG-CoA reductase activity at the post-transcriptional level. Considered together, the data suggest that the hypolipidemic action of lifibrol may, at least in part, be mediated by sterol-independent stimulation of the LDL receptor pathway. A potential advantage of lifibrol is that therapeutic concentrations do not interfere with the production of mevalonate which is required not only to synthesize sterols but also as a precursor of electron transport moieties, glycoproteins and farnesylated proteins.
Atherosclerosis 2000 Nov
PMID:The effects of lifibrol (K12.148) on the cholesterol metabolism of cultured cells: evidence for sterol independent stimulation of the LDL receptor pathway. 1105 1

The pharmacological profile of F 12511 (S)-2',3', 5'-trimethyl-4'-hydroxy-alpha-dodecylthio-phenylacetanilide, a new inhibitor of acyl-CoA: cholesterol acyltransferase (EC 2.3.1.26; ACAT), was evaluated by using different in vitro and in vivo models. In vitro, F 12511 was shown to be a highly potent inhibitor of ACAT activity in microsomal preparations from various animal species as well as of cholesterol esterification in relevant human cell lines in culture. The concentrations of F 12511 required to produce 50% inhibition of ACAT activity (IC(50) values) in microsomal preparations ranged from 41nM for hypercholesterolemic rabbit intestine to 223 nM for normocholesterolemic hamster liver. In whole cell assays using hepatic (Hep G2), intestinal (CaCo-2) and macrophagic (THP-1) cell lines, F 12511 inhibited ACAT activity with IC(50) values of 3, 7, and 71 nM, respectively. In vivo, orally administered F 12511 displayed high potency and efficacy as an antihypercholesterolemic compound in different cholesterol-fed animals (rat, guinea-pig, rabbit). For instance, in guinea-pigs the dose required to reduce plasma cholesterol levels by 30% (ED(30) value) was 0.008 mg.kg(-1.) In rabbits, an animal species prone to atherosclerosis, the hypocholesterolemic effect was accompanied by a dose-related reduction in the incidence of aortic fatty streaks that reached asymptote at 2.5 mg.kg(-1) and by an improvement of the impaired endothelial function. When given orally to chow-fed hamsters, F 12511 elicited a dose-related decrease in plasma cholesterol from 9% at 0.63 mg.kg(-1) up to 31% at 40 mg.kg(-1) associated with a preferential reduction in atherogenic lipoproteins, very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Moreover, in the same dose range, F 12511 decreased hepatic cholesteryl ester concentrations and reduced liver ex vivo ACAT activity. By using a bioassay, ACAT inhibitory activity was present in plasma of treated hamsters 1 hr after oral administration of F 12511. Hence, the results in chow-fed hamsters are consistent with systemic and direct hepatic effects of F 12511. In guinea-pigs, an adreno-sensitive species, F 12511 did not impair the adrenal function (adrenocorticotrophic hormone challenge) at doses up to 2.5 mg.kg(-1,) far higher than those eliciting hypocholesterolemic effects in the same species. In conclusion, the results suggest that F 12511, a powerful and systemic ACAT inhibitor, constitutes an appropriate tool to determine whether the inhibition of ACAT constitutes an effective therapy for the treatment of hypercholesterolemia and of atherosclerosis in man.
 ...
PMID:Pharmacological profile of F 12511, (S)-2',3', 5'-trimethyl-4'-hydroxy-alpha-dodecylthioacetanilide a powerful and systemic acylcoenzyme A: cholesterol acyltransferase inhibitor. 1113 14

The short- and long-term in vitro effects of the hydroxymethylglutaryl-CoA reductase inhibitor atorvastatin, compared with lovastatin and simvastatin on VLDL secretion, and on the formation and the neutral and acid lysosomal hydrolysis of cholesteryl esters was investigated in rat liver hepatocytes maintained in suspension (2 or 4 h) or cultured in monolayers (24 h). All statins time-dependently reduced [14C]oleate incorporation into cholesteryl esters, but when exogenous cholesterol was added only atorvastatin caused an immediate transient decrease in hepatocyte ACAT activity. Activity of the lysosomal, microsomal and cytosolic CEH isoforms was unaffected by the hepatocyte treatments. Statins reduced free and esterified cholesterol mass in hepatocyte microsomes after 2 h, and this was followed by a modest decline in VLDL cholesteryl esters, whilst secretion of VLDL apoB and triglycerides was unaltered. However, after 24 h of treatment, statins caused generalized 20-40% decreases in the secretion of VLDL apoB, cholesterol and triglycerides, with the reduction in apoB48 secretion being significantly superior to that caused in apoB100. The mean diameter of secreted VLDL was not modified by either duration or drug treatment. Additional studies with subcellular fractions demonstrated that statins have a direct selective effect on the enzymes governing the cholesterol-cholesteryl ester cycle, with the exception of the microsomal CEH. Atorvastatin, lovastatin and simvastatin inhibited ACAT activity in microsomes by 50% at doses of 250, 100 and 50 microM, respectively. The cytosolic CEH elicited a biphasic profile of activity with activations up to 100 microM statin and inhibitions above 250 microM, and the lysosomal CEH was only inhibited by atorvastatin at a dose of 100 microM or more. We conclude that a prolonged, but not a short, limited availability of hepatocyte cholesterol derived from the endogenous synthesis reduces VLDL secretion, and that reactivity of statins at the cellular level are more similar than reactivity at the subcellular level as regards the cholesterol-cholesteryl ester cycle.
Atherosclerosis 2000 Dec
PMID:Short- and long-term effects of atorvastatin, lovastatin and simvastatin on the cellular metabolism of cholesteryl esters and VLDL secretion in rat hepatocytes. 1116 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>