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)

The effects produced by the two pyrimidine derivatives pyridinol carbamate (parmidine) and xymedon on cholesterol metabolism and experimental atherosclerosis were comparatively studied in rabbits. The rabbits were fed either a chow containing cholesterol (200 mg/kg body weight) or the same diet also containing xymedon (30 mg/kg body weight) or pyridinol carbamate (30 mg/kg body weight). Total plasma cholesterol showed 5.5- and 4.7-fold increases in the rabbits receiving only cholesterol or cholesterol + pyridinol carbamate, respectively, as compared with that in the animals on a standard laboratory chow. In the rabbits given cholesterol+xymedon, cholesterol levels were 24% less than that in the animals taking cholesterol alone. In these animals, the aortic atherosclerotic damage index (ADI) was equal to 24.1%, which was 1.8-fold less than that in the cholesterol-fed rabbits. In the rabbits given cholesterol+pyridinol carbamate, ADI was decreased by 1.7 times, but it did not differ from that in the hypocholesterolemic rabbits. At the same time xymidone and pyridinol carbamate reduced the hepatic levels of total and esterified cholesterol. To elucidate the mechanism of action of xymedon, it was studied for effects on cholesterol metabolism in cultured rabbit hepatocytes and murine macrophage J774. Xymedon did not alter the esterification and other parameters of cholesterol metabolism in the cultured hepatocytes. It is suggested that the hypocholesterolemic effect was realized at the level of intestinal rather than hepatic cholesterol metabolic changes. The investigations made on the murine macrophage J744 showed that xymedone reduced cholesterol esterification in macrophages, evidently by inhibiting the activity of the enzyme acyl-CoA: cholesterol acyltransferase. The anti-atherosclerotic effect of xymedon seems to result from reductions in plasma cholesterol levels and cholesterol esterification in blood vascular cells.
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PMID:[The effect of ximedon on cholesterol metabolism and experimental atherosclerosis in rabbits]. 778 89

To investigate the effect of dietary eicosapentaenoic acid (EPA) on plasma lipoprotein levels, lecithin:cholesterol acyltransferase (LCAT) activity and liver acetyl CoA carboxylase activity, highly concentrated EPA (78%) purified from sardine oil was fed to stroke-prone spontaneously hypertensive rats (SHRSP) for 30 days. Significantly (P < 0.05) lower systolic blood pressure and plasma total cholesterol were observed in rats fed an EPA diet. In addition, higher HDL cholesterol and lower VLDL cholesterol levels were found in rats fed the EPA diet as compared with rats fed the control diet. However, no significant change of plasma LDL cholesterol was observed in rats between the two dietary groups. EPA supplementation increased the activity of plasma LCAT in rats. In addition, rats fed an EPA diet had lower liver total lipids and adipose tissue weights. However, higher liver acetyl CoA carboxylase activity was observed in rats fed the EPA diet. Results from the present study suggest that dietary EPA might stimulate the plasma lipoprotein metabolism and also alter lipogenesis in the liver of SHRSP rats.
Atherosclerosis 1994 Mar
PMID:Lipoprotein, lecithin:cholesterol acyl transferase and acetyl CoA carboxylase in stroke-prone spontaneously hypertensive rats fed a diet high in eicosapentaenoic acid. 791 8

Clearance of excess cholesterol from cells by HDL is facilitated by the interaction of HDL apolipoproteins with cell-surface binding sites or receptors, a process that may be important in preventing atherosclerosis. In this study, synthetic peptides containing 18-mer amphipathic helices of the class found in HDL apolipoproteins (class A) were tested for their abilities to remove cholesterol and phospholipid from cultured sterol-laden fibroblasts and macrophages and to interact with cell-surface HDL binding sites. Lipid-free peptides containing two identical tandem repeats of class A amphipathic helices promoted cholesterol and phospholipid efflux from cells and depleted cellular cholesterol accessible for esterification by acyl CoA/cholesterol acyltransferase, similar to what was observed for purified apolipoprotein A-I. Peptide-mediated removal of plasma membrane cholesterol and depletion of acyl CoA/cholesterol acyltransferase-accessible cholesterol appeared to occur by separate mechanisms, as the latter process was less dependent on extracellular phospholipid. The dimeric amphipathic helical peptides also competed for high-affinity HDL binding sites on cholesterol-loaded fibroblasts and displayed saturable high-affinity binding to the cell surface. In contrast, peptides with a single helix had little or no ability to remove cellular cholesterol and phospholipid, or to interact with HDL binding sites, suggesting that cooperativity between two or more helical repeats is required for these activities. Thus, synthetic peptides comprising dimers of a structural motif common to exchangeable apolipoproteins can mimic apolipoprotein A-I in both binding to putative cell-surface receptors and clearing cholesterol from cells.
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PMID:Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol. 792 49

To establish whether lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, exhibits a specific effect on apolipoprotein (apo) A- and apoB-containing lipoproteins, 63 subjects, a subset of the 270 Monitored Atherosclerosis Regression Study (MARS) patients with hypercholesterolemia (190 to 295 mg/dL) and documented coronary artery disease, were randomized into either lovastatin 40 mg twice daily or matching placebo tablets twice daily. Both groups consumed a diet containing 27% calories as fat (polyunsaturated fat/saturated fat ratio, 2.85) and a daily cholesterol intake of less than 250 mg. The plasma lipid and apolipoprotein profiles were determined at the time of randomization and after 2 years of treatment, and the levels of apoA- and apoB-containing lipoprotein families were measured after 2 years of treatment. After this treatment period, the drug group was characterized in comparison with the placebo group by significantly reduced levels of total cholesterol (33%), triglycerides (30%), very-low-density lipoprotein cholesterol (36%), low-density lipoprotein cholesterol (43%), apoB (36%), apoC-III (18%), and apoE (17%) and slightly but insignificantly increased levels of high-density lipoprotein cholesterol (6%) and apoA-I (1%). The 2-year levels of lipoprotein containing apoA-I but no apoA-II (LpA-I) and lipoprotein containing both apoA-I and apoA-II (LpA-I/A-II) particles separated by immunoaffinity chromatography on an anti-apoA-II immunosorber did not differ between the two treatment groups. However, the apoB-containing lipoprotein (Lp) families defined by apolipoprotein composition and separated by immunoaffinity chromatography on anti-apoA-II and anti-apoC-III immunosorbers were affected in a selective manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of lovastatin on ApoA- and ApoB-containing lipoproteins. Families in a subpopulation of patients participating in the Monitored Atherosclerosis Regression Study (MARS). 798 Nov 78

Previous studies have shown that both cholesterol synthesis and the activity of hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, are increased in the small intestine of a wide variety of different animal models of diabetes. In the present study, we demonstrate that the mass of HMG CoA reductase protein is increased in the small intestine of both streptozocin-induced diabetic rats (2.5-fold) and streptozocin/alloxan-induced diabetic dogs (2.4-fold). These increases in HMG CoA reductase protein mass are of a magnitude similar to the previously observed increases in either HMG CoA reductase activity and/or cholesterol synthesis in the small intestine of diabetic animals. Furthermore, mRNA levels for HMG CoA reductase in the small intestine of diabetic rats and diabetic dogs are increased 2.1- and 1.7-fold, respectively. These results suggest that the increase in HMG CoA reductase protein levels in the small intestine of diabetic animals is due to an increase in mRNA levels. In contrast, mRNA levels for HMG CoA reductase in the liver of diabetic rats are not increased. Additionally, mRNA levels for the low-density lipoprotein (LDL) receptor are also increased in the small intestine of diabetic animals (rats, 43%; dogs, 59%). The increase in small-intestinal cholesterol synthesis has the potential for adversely affecting lipoprotein metabolism and increasing the risk of atherosclerosis in diabetes.
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PMID:Diabetes increases hepatic hydroxymethyl glutaryl coenzyme A reductase protein and mRNA levels in the small intestine. 815 2

It has been postulated that oxidatively modified low-density lipoprotein (LDL) contributes to the genesis of atherosclerosis. Ubiquinone has been suggested to be an important physiological lipid-soluble antioxidant and is found in LDL fractions in the blood. We measured plasma level of ubiquinone using high-performance liquid chromatography and plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in 245 normal subjects (186 males, 59 females) and in 104 patients (55 males, 49 females) who had coronary artery disease not receiving pravastatin and 29 patients (12 males, 17 females) receiving pravastatin. In the normal subjects, the plasma ubiquinone levels did not vary with age. In the patient groups, the plasma total cholesterol and LDL levels were higher and the plasma ubiquinone level lower than in the normal subject group. The LDL/ubiquinone ratio was higher in the patient groups. We found that ubiquinone level, either alone or when expressed in relation to LDL levels, was significantly lower in the patient groups compared with the normal subject group. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor is thought to prevent atherosclerosis, however, it also inhibits ubiquinone production. The present study revealed that HMG CoA reductase inhibitor decreased plasma cholesterol level, and that it did not improve either the ubiquinone level or the LDL/ubiquinone ratio. From these results, the LDL/ubiquinone ratio is likely to be a risk factor for atherogenesis, and administration of ubiquinone to patients at risk might be needed.
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PMID:Coenzyme Q10 and coronary artery disease. 824 93

Hepatic lipase-deficient subjects in the Ontario kindred are compound heterozygotes for hepatic lipase mutations (Ser267-->Phe and Thr383-->Met). Cholesteryl ester-rich beta-very-low-density lipoprotein (beta-VLDL) accumulates in plasma and such subjects have premature atherosclerosis. To determine a possible mechanism, we hypothesized that hepatic lipase-deficient beta-VLDL, homozygous for apolipoprotein (apo) E3, would cause cholesteryl ester accumulation and foam cell formation in macrophages. beta-VLDL and pre-beta-VLDL were isolated by Pevikon electrophoresis and incubated with J774 macrophages, cells that do not secrete apoE. beta-VLDL increased cellular cholesteryl ester content 13-fold, whereas pre-beta-VLDL increased cholesteryl ester sevenfold. beta-VLDL increased acyl CoA:cholesterol acyltransferase activity fourfold (measured as [14C]oleate incorporation into cholesteryl ester). Preincubation of hepatic lipase-deficient beta-VLDL with the anti-apoE monoclonal antibody 1D7, which inhibits binding of apoE to low-density lipoprotein receptors, inhibited cellular cholesteryl ester accumulation by 75%, whereas the anti-apoB blocking monoclonal antibody 5E11 failed to inhibit cellular cholesteryl ester accumulation. In contrast to hepatic lipase deficiency, beta-VLDL from type III subjects (E2/E2) failed to increase cellular cholesteryl ester or acyl CoA:cholesterol acyltransferase more than 1.5-fold. Thus, hepatic lipase-deficient beta-VLDL readily induces cholesteryl ester accumulation in J774 macrophages, a process mediated by functional apoE3. This may explain the premature atherosclerosis observed in this kindred.
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PMID:Beta-VLDL in hepatic lipase deficiency induces apoE-mediated cholesterol ester accumulation in macrophages. 836 12

Atherosclerotic lesion development may be altered indirectly by regulating plasma cholesterol or directly by inhibition of acyl-CoA cholesterol O-acyltransferase (ACAT) within cells of the artery. Yucatan micropigs were meal-fed a 2% cholesterol, 8% peanut oil, 8% coconut oil purified diet for 1 month prior to administration of the potent, bioavailable ACAT inhibitor CI-976, and induction of atherosclerotic lesions by chronic endothelial damage. After 84-108 days of therapy, CI-976 decreased mean plasma VLDL-cholesterol 85-91% and cumulative VLDL-exposure (area under VLDL-time curve) by 65%. However, overall plasma total, LDL and HDL cholesterol and triglyceride levels were unchanged. CI-976 decreased liver cholesteryl ester (CE) content 65% without significantly affecting adrenal CE content. The CE content of the injured left femoral, left iliac and abdominal aorta and uninjured right femoral and iliac arteries and thoracic aorta was reduced 62-78% by CI-976. Systemic plasma CI-976 levels measured 24 h post-dose ranged from 2.26 to 4.05 micrograms/ml and significantly correlated with the reduction in both VLDL and vessel CE content. Thus, we conclude that inhibition of ACAT can blunt the cholesteryl ester enrichment of developing atherosclerotic lesions by preventing reesterification and storage of lipoprotein cholesterol within vascular cells and by reducing the plasma level and delivery to the arterial wall of such atherogenic lipoproteins as VLDL.
Atherosclerosis 1993 Mar
PMID:Inhibition of acyl-CoA cholesterol O-acyltransferase reduces the cholesteryl ester enrichment of atherosclerotic lesions in the Yucatan micropig. 850 46

In mutant analbuminaemic rats (NAR), females demonstrate a more marked hypertriglyceridaemia than males. Ovariectomy decreases triglyceride levels in female NAR. We measured triglyceride secretion rates in vivo as well as the activity of acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS) in hepatic cytosol obtained from female control Sprague-Dawley (SD) rats and NAR with or without ovariectomy. NAR were severely hyperlipidaemic, and triglyceride, cholesterol, apolipoprotein A-I and plasma protein concentrations levels were decreased (all P < 0.01) by ovariectomy. Only triglyceride levels were decreased by ovariectomy in the SD rats (P < 0.05). Oestradiol treatment in ovariectomized NAR restored plasma protein and triglyceride concentrations to levels similar to those observed in intact female NAR and caused a marked increase in plasma cholesterol. Ovariectomy in NAR reduced lipoprotein triglycerides and cholesterol in VLDL, IDL and LDL1, but had little effect on the triglyceride-cholesterol ratio of these particles. Both ACC and FAS activities were markedly increased in NAR vs. SD rats (P < 0.01). This increase was partially corrected by ovariectomy. There was no significant effect of ovariectomy on ACC or FAS activity in the SD rats. Triglyceride secretion rates were significantly increased in NAR vs. SD rats (135 +/- 10 vs. 103 +/- 12 nmol/min per 100 g body weight; P < 0.05). Ovariectomy markedly decreased triglyceride secretion rate in NAR to 69 +/- 6 (P < 0.01), but not in SD rats (92 +/- 8 nmol/min per 100 g body weight, NS). Oestradiol treatment in ovariectomized SD rats restored triglyceride levels but had no significant effect on triglyceride secretion rate (106 +/- 23 nmol/min per 100 g).(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Sep
PMID:Ovariectomy decreases plasma triglyceride levels in analbuminaemic rats by lowering hepatic triglyceride secretion. 854 55

The formation of macrophage-derived foam cells is central to the development of fatty streaks within the arterial wall, and to the progression of atherosclerosis. The unregulated deposition of cholesteryl esters, as lipid droplets within the cytoplasm of these cells, is responsible for the formation of foam cells; this process is thought to be regulated by the balance between cholesterol esterification, by acyl CoA:cholesterol acyltransferase (ACAT), and hydrolysis, by neutral cholesteryl ester hydrolase (nCEH). This study examines the importance of the balance between these two enzymes in determining the efflux of cholesterol from human (THP-1) macrophages. The presence of modified lipoprotein, or of 25-hydroxycholesterol, markedly increased cholesterol esterification in these cells and these effects were potently inhibited by the presence of the ACAT inhibitor, 447C88. In the absence of HDL, an acceptor particle, there was little or no hydrolysis of the cholesteryl ester pool and no efflux of cholesterol to the extracellular milieu; addition of HDL led to a partial (36%) reduction in cholesteryl esters, an effect which was not enhanced by the inhibition of ACAT. This suggested that the stored cholesteryl esters in human (THP-1) macrophages, unlike those in mouse peritoneal macrophages, were relatively resistant to removal by efflux to HDL. Efflux of newly synthesised free cholesterol from these macrophages was increased by HDL in a saturable manner, suggesting that the lack of reduction of stored cholesteryl esters was due to impaired mobilisation of cholesteryl esters to free cholesterol via nCEH. Indeed, nCEH activity in these macrophages was much lower than in mouse peritoneal macrophages, and appeared to be down-regulated in the presence of 25-hydroxycholesterol or modified lipoproteins; this loss of nCEH activity was prevented by the ACAT inhibitor 447C88. The efflux of stored cholesteryl esters from THP-1 macrophages therefore appears to be limited by the activity of nCEH.
Atherosclerosis 1996 Feb
PMID:Impaired mobilisation of cholesterol from stored cholesteryl esters in human (THP-1) macrophages. 864 54


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