| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients Yeo, K. R., W. W. Yeo, et al. (1999), Br J Clin Pharmacol 48(4): 610-5. Abstract: AIMS: To investigate whether an interaction between diltiazem and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may enhance the cholesterol-lowering response to simvastatin in diltiazem-treated patients. METHODS: One hundred and thirty-five patients attending the Sheffield hypertension clinic who started consecutively on simvastatin for primary or secondary prevention of coronary heart disease (CHD) during the 2 years June, 1996-May 1998 were surveyed. From the clinic records we extracted and recorded absolute and percentage cholesterol responses to the starting dose of simvastatin and coprescription of diltiazem. RESULTS: The cholesterol reduction for the 19 patients on diltiazem was 33.3% compared with 24.7% in the remaining 116 patients (median difference 8.6%, 95% CI 1.1-12.2%, P<0.02). The interindividual variability of cholesterol response to simvastatin was greater for patients not taking diltiazem than for those patients taking diltiazem. The ratio of the variances in response for the nondiltiazem group relative to the diltiazem group was 1.34 at 10 mg simvastatin daily (not significant, 95% CI 0.16-4.11), and 3.42 at 20 mg daily (P<0.01, 95% CI 1.26-7.18). Concurrent diltiazem therapy (P<0.04), age (P=0.001) and starting dose of simvastatin (P=0.002) were found to be significant independent predictors of percentage cholesterol response. CONCLUSIONS: Patients who take both simvastatin and diltiazem may need lower doses of simvastatin to achieve the recommended reduction in cholesterol. The pharmacokinetic and pharmacodynamic aspects of this interaction need further study to confirm an enhanced effect on cholesterol reduction, and exclude an increased risk of adverse events. |
| Enhanced coronary vasoconstrictive response to serotonin subsides after removal of dietary cholesterol in atherosclerotic monkeys Lamping, K. G., D. J. Piegors, et al. (1994), Arterioscler Thromb 14(6): 951-7. Abstract: Constriction in response to serotonin is enhanced in the coronary arteries of atherosclerotic monkeys. The main objective of the present study was to determine whether abnormal responses to serotonin in atherosclerosis are reversed following removal of dietary cholesterol. In addition, we examined the effect of an atherogenic diet and reduction in dietary cholesterol on vascular responses to activation of ATP-sensitive K+ channels with aprikalim. Diameters of small coronary arteries were measured on the epicardial surface of the left ventricle in vivo by using stroboscopic illumination synchronized to the heart cycle to visually freeze the motion of the heart. Diameters were measured with a microscope-video system during topical application of two vasoconstrictor agonists, serotonin and the thromboxane mimetic U46619, and the vasodilator agonists aprikalim and nitroprusside. Responses were compared in normal (n = 9), atherosclerotic (n = 14; high-cholesterol diet), and regression (n = 8; high-cholesterol diet followed by normal diet) monkeys. Constriction of coronary arteries in response to serotonin was enhanced in monkeys on an atherogenic diet and was normal in regression monkeys. Vasoconstriction in response to U46619 and vasodilation in response to nitroprusside and aprikalim were not altered by atherosclerosis. Thus, abnormal vascular responses to serotonin in small coronary arteries of atherosclerotic monkeys without morphological evidence of disease can be reversed to normal by reducing dietary cholesterol. |
| Enhanced development of atherosclerosis in cholesterol-fed rabbits by suppression of cell-mediated immunity Roselaar, S. E., G. Schonfeld, et al. (1995), J Clin Invest 96(3): 1389-94. Abstract: T lymphocytes are present in atherosclerotic lesions, but the role of this cell type in the disease process has not been determined. To determine whether cell-mediated immunity influences atherogenesis, New Zealand White rabbits fed a cholesterol-supplemented diet (0.5% wt/wt) were treated with cyclosporin A (n = 20) or vehicle alone (n = 16) for 12 wk. The dose of cyclosporin A was adjusted so that a blood concentration between 100 and 200 ng/ml was maintained to achieve a selective action T-lymphocytes. Effectiveness of immunosuppression in cyclosporin A-treated rabbits was confirmed by allogeneic skin graft survival. Cyclosporin A administration did not affect total plasma lipid concentrations, body weight, or renal function. Percentage of aortic intimal area covered with atherosclerotic lesions was increased significantly by immunosuppression in both the arch region (75 +/- 3% mean +/- SEM compared with 60 +/- 5% in controls; P < 0.01) and the thoracic region (47 +/- 7% vs 27 +/- 6%; P = 0.04). Enhanced atherogenesis was not associated with diminished numbers of T lymphocytes in lesions, changes in T lymphocyte subtype, or any discernible change in cellular composition. Humoral immune responses to oxidized LDL were similar in the two groups: serum titres of autoantibodies against malondialdehyde-modified LDL were equivalent. These data demonstrate that cyclosporin A-induced suppression of cell-mediated immunity increased the development of macrophage-rich atherosclerotic lesions in cholesterol-fed rabbits. |
| Enhanced efficacy of sitostanol-containing versus sitostanol-free phytosterol mixtures in altering lipoprotein cholesterol levels and synthesis in rats Ling, W. H. and P. J. Jones (1995), Atherosclerosis 118(2): 319-31. Abstract: To investigate the action and mechanism of a dietary phytosterol mixture naturally containing sitostanol, derived from tall-oil, on circulating cholesterol and lipoprotein levels, five groups of rats were fed a control elemental diet (group 1), a control elemental diet with 1% cholesterol alone (group 2) or with sitostanol mixtures or a sitostanol-free mixture supplemented at 0.2% (group 3), 0.5% (group 4) or 1% (group 5) of dietary levels. One per cent supplementation of sitostanol (21%) compared with sitostanol-free mixtures decreased (P < 0.02) total serum cholesterol. Dietary sitostanol (16% or 21%) mixture at 1% dietary levels decreased (P < 0.05) low density lipoprotein (LDL) cholesterol and increased (P < 0.05) high density lipoprotein (HDL) cholesterol levels. The decrease of LDL and increase of HDL cholesterol were correlated (P < 0.01) with the level of sitostanol mixture in the diet. Consumption of the sitostanol-containing mixture (1% dietary levels) caused a compensatory increase in cholesterol synthesis as indicated by elevated (P < 0.05) lathosterol/ cholesterol ratios in plasma and hepatic cholesterol fractional synthesis rate (FSR) (P < 0.02). Both sitostanol and sitostanol-free mixtures at 0.5% or 1% dietary intake levels increased plasma campesterol and beta-sitosterol levels, while plasma sitostanol levels were negligible. The absence of sitostanol in plasma and the increase in cholesterol synthesis induced by dietary sitostanol mixtures in addition to elevation of plasma campesterol and beta-sitosterol by sitostanol or sitostanol-free mixtures suggest that sitostanol mixtures effectively modify circulating lipoprotein cholesterol concentrations at the level of the intestine, rather than internally at the level of cholesterogenesis. |
| Enhanced efflux of cholesterol from ABCA1-expressing macrophages to serum from type IV hypertriglyceridemic subjects Fournier, N., O. Francone, et al. (2003), Atherosclerosis 171(2): 287-93. Abstract: Since elevated plasma triglycerides (TGs) are an independent cardiovascular risk factor, we have compared the cholesterol efflux potential of sera from asymptomatic hypertriglyceridemic (HTG) type IIb, type IV or normolipidemic (NLP) individuals using two different cell systems. In both type IIb and IV HTG, the efflux of cholesterol from SR-BI-rich Fu5AH cells was similar to that obtained with NLP. The maintenance of efflux efficiency in spite of reduced HDL-cholesterol levels can be mainly attributed to the relative enrichment of HDL with phospholipid. In the J774 macrophage cell system, pretreatment with cAMP, which upregulates ABCA1, induced a markedly higher increase in efflux to type IV sera compared with type IIb or NLP. In addition, type IV sera exhibited two-fold higher pre-beta HDL relative concentration (percentage of total apo AI) compared with NLP. Moreover, positive correlations were established between ABCA1-mediated efflux and the serum pre-beta HDL levels or TG concentrations. Thus, the hyperTGemia is associated with a higher fraction of apo AI recovered as pre-beta HDL which appear to be partly responsible for enhanced efflux obtained upon the cAMP stimulation of J774 cells. In conclusion, we demonstrated for the first time that the ABCA1-expressing J774 cell system is responsive to the percent of apo AI present in human serum as pre-beta HDL. Our results suggest that high-plasma TG, accompanied by low HDL may not result in an impaired cholesterol efflux capacity. |
| Enhanced expression of tissue factor activity in the atherosclerotic aortas of cholesterol-fed rabbits Kato, K., Y. A. Elsayed, et al. (1996), Thromb Res 82(4): 335-47. Abstract: Tissue factor (TF) is an initiation cofactor of the extrinsic pathway of coagulation. Although the overexpression of TF antigen and mRNA have been previously demonstrated in atherosclerotic lesions using both immunohistochemical and in situ hybridization techniques, it still remains unclear as to whether TF activity is overexpressed in atherosclerotic plaque in vivo. In thoracic aortas obtained from cholesterol-fed rabbits for 10-20 weeks, the TF-mediated activation of factor X was quantitatively assessed on the intimal surface of the aortas ex vivo using a chromogenic substrate S-2222 and the findings were then compared with the immunohistochemical distribution of TF antigen. Non-atherosclerotic intimas showed only a weak amount of TF activity, while the adventitia contained a significantly high amount of activity. In the atherosclerotic intimas where TF antigen was overexpressed by foamy and non-foamy macrophages and smooth muscle cells but not by endothelial cells, TF activity was apparently enhanced to a level similar to that in the adventitia. Scanning electron microscopy revealed a perturbation of the intimal surface of the atherosclerotic aorta. These findings suggest that TF activity is apparently enhanced in subendothelial atherosclerotic lesions and, therefore, endothelial denudation, which results in the exposure of active TF to flowing blood, leads to thrombosis and its sequelae in atherosclerotic lesions. |
| Enhanced hepatic uptake and processing of cholesterol esters from low density lipoprotein by specific lactosaminated Fab fragments Bijsterbosch, M. K., F. Bernini, et al. (1991), Arterioscler Thromb 11(6): 1806-13. Abstract: Reduction of the blood levels of low density lipoprotein (LDL) is important for lowering the incidence of atherosclerosis. In this study, LDL was directed to rat parenchymal liver cells by lactosaminated Fab fragments of anti-apolipoprotein B antibodies (LacFab). We followed the fate of intravenously injected complexes of LacFab and 3Hcholesteryl oleate-labeled LDL. Complexing of LacFab to LDL led to rapid disappearance of LDL from the circulation. At 30 minutes after injection, the liver contained 58.5 +/- 9.0% of the injected dose (at that time the liver contained only 5.7 +/- 2.2% of an injected dose of free LDL). Liver uptake was blocked by N-acetylgalactosamine but not by N-acetylglucosamine, which indicates that galactose-specific recognition sites are responsible for the LacFab-induced hepatic uptake. By isolating liver cells, it was found that parenchymal, endothelial, and Kupffer cells account for 87%, 3%, and 10% of the total hepatic uptake, respectively. Subcellular fractionation of the liver indicated that the complexes are rapidly internalized and transported to lysosomes. Within 1 hour after injection, virtually all the 3Hcholesteryl oleate of the internalized LDL was hydrolyzed; hydrolysis was followed by excretion of radioactivity into the bile. Compared with rats injected with native 3Hcholesteryl oleate-labeled LDL, eight times as much radioactivity was excreted into the bile during the first 4 hours after the injection of LacFab-complexed 3Hcholesteryl oleate-labeled LDL. Thus, LacFab induces enhanced hepatic uptake of LDL via galactose receptors on the parenchymal cells, followed by processing in lysosomes and excretion into the bile. In this way, LacFab induces an increased irreversible removal of LDL cholesterol from the body. |
| Enhanced hydrolysis of phosphatidylcholine by human group II non-pancreatic secreted phospholipase A2 as a result of interfacial activation by specific anions. Potential role of cholesterol sulphate Kinkaid, A. R. and D. C. Wilton (1995), Biochem J 308 (Pt 2): 507-12. Abstract: The extracellular concentration of the Group II human non-pancreatic secreted phospholipase A2 (hnpsPLA2) is elevated in a variety of inflammatory disorders. This enzyme is remarkable because it demonstrates almost zero activity with egg phosphatidylcholine (PC) or synthetic dioleoyl-phosphatidylcholine (DOPC) as substrate, but expresses high activity with the anionic phospholipid dioleoyl-phosphatidylglycerol (DOPG), a feature shared with the Group II enzyme from rat liver. The presence of certain membrane-bound anions can enhance hydrolysis of PC by the mammalian secreted PLA2S. In this study the ability of various non-polar anions to stimulate DOPC hydrolysis by secreted PLA2S has been investigated. The naturally occurring membrane anion, cholesterol sulphate, was particularly effective in stimulating the hydrolysis of both DOPC and also 1-stearoyl-2-arachidonyl phosphatidylcholine by hnpsPLA2. Activation of DOPC hydrolysis was also achieved with dioleoyl-phosphatidylserine (DOPS); however, DOPS was less effective than cholesterol sulphate. In contrast, the dianion dioleoyl-phosphatidic acid, a known activator of pig pancreatic PLA2, failed to activate the human enzyme. It remains to be established whether cell plasma-membrane hydrolysis by extracellular hnpsPLA2 can be activated in vivo by the presence of suitable membrane anions such as cholesterol sulphate and thus promote an inflammatory response within the cell. |
| Enhanced insulin secretion and cholesterol metabolism in congenic strains of the spontaneously diabetic (Type 2) Goto Kakizaki rat are controlled by independent genetic loci in rat chromosome 8 Wallis, R. H., K. J. Wallace, et al. (2004), Diabetologia 47(6): 1096-106. Abstract: AIMS/HYPOTHESIS: Genetic investigations in the spontaneously diabetic (Type 2) Goto Kakizaki (GK) rat have identified quantitative trait loci (QTL) for diabetes-related phenotypes. The aims of this study were to refine the chromosomal mapping of a QTL (Nidd/gk5) identified in chromosome 8 of the GK rat and to define a pathophysiological profile of GK gene variants underlying the QTL effects in congenics. METHODS: Genetic linkage analysis was carried out with chromosome 8 markers genotyped in a GKxBN F2 intercross previously used to map diabetes QTL. Two congenic strains were designed to contain GK haplotypes in the region of Nidd/gk5 transferred onto a Brown Norway (BN) genetic background, and a broad spectrum of diabetes phenotypes were characterised in the animals. RESULTS: Results from QTL mapping suggest that variations in glucose-stimulated insulin secretion in vivo, and in body weight are controlled by different chromosome 8 loci (LOD3.53; p=0.0004 and LOD4.19; p=0.00007, respectively). Extensive physiological screening in male and female congenics at 12 and 24 weeks revealed the existence of GK variants at the locus Nidd/gk5, independently responsible for significantly enhanced insulin secretion and increased levels of plasma triglycerides, phospholipids and HDL, LDL and total cholesterol. Sequence polymorphisms detected between the BN and GK strains in genes encoding ApoAI, AIV, CIII and Lipc do not account for these effects. CONCLUSIONS/INTERPRETATION: We refined the localisation of the QTL Nidd/gk5 and its pathophysiological characteristics in congenic strains derived for the locus. These congenic strains provide novel models for testing the contribution of a subset of GK alleles on diabetes phenotypes and for identifying diabetes susceptibility genes. |
| Enhanced low-density lipoprotein cholesterol reduction and cost-effectiveness by low-dose colestipol plus lovastatin combination therapy Schrott, H. G., E. A. Stein, et al. (1995), Am J Cardiol 75(1): 34-9. Abstract: A total of 96 patients with moderate elevations of low-density lipoprotein (LDL) cholesterol were randomly assigned to 4 different double-blind treatment regimens: placebo; colestipol 5 g and lovastatin 20 mg/day (C5 + L20); colestipol 10 g and lovastatin 20 mg/day (C10 + L20); and lovastatin 40 mg/day (L40). During 12 weeks of therapy, C10 + L20 achieved the greatest reduction in total cholesterol (-32%) and LDL cholesterol (-48%) levels from baseline. This combination also exhibited significantly greater reductions in LDL cholesterol levels than the C5 + L20 and L40 groups (p < 0.01). The differences in total and LDL cholesterol reduction between the C5 + L20 and L40 groups were not significant. Similar changes and differences between treatments were seen in apolipoprotein B levels. Whereas mean total apolipoprotein A-I levels increased with all treatments (p < 0.05), lipoprotein particles A-I were significantly increased in the C10 + L20 group (p < 0.01) only. Results demonstrate that the combination of low-dose lovastatin (20 mg/day) with low-dose colestipol (5 or 10 g/day) produces LDL cholesterol reductions equal to or greater than higher doses of lovastatin (40 mg/day). In addition, low-dose combinations are > 25% more cost-effective than high-dose monotherapy. |
| Enhanced low-density lipoprotein degradation and cholesterol synthesis in monocyte-derived macrophages of patients with adult xanthogranulomatosis Bergman, R., M. Aviram, et al. (1993), J Invest Dermatol 101(6): 880-2. Abstract: Adult xanthogranulomatosis is an uncommon disorder in which dermal macrophages accumulate cholesterol intracellularly despite normal plasma cholesterol levels. In an attempt to elucidate an underlying biochemical abnormality in this disorder, we studied the rates of 125I-labeled low-density lipoprotein degradation, and intracellular cholesterol synthesis, in human monocyte-derived macrophages of three patients with adult xanthogranulomatosis. In all three patients, the rates of cellular 125I-low-density lipoprotein degradation and of cholesterol synthesis were 22-37% and 14-84% higher than those of the respective normal controls (p < 0.01). These findings suggest that in MDM of adult xanthogranulomatosis patients, the uptake and degradation of low-density lipoprotein-derived cholesterol and intracellular cholesterol biosynthesis are enhanced. Because dermal macrophages are derived from blood monocytes, it is possible that such an enhancement might play a role in the accumulation of cholesteryl esters in the macrophages that form the xanthogranulomatosis lesions. |
| Enhanced plasma cholesterol lowering effect of retrovirus-mediated LDL receptor gene transfer to WHHL rabbit liver after improved surgical technique and stimulation of hepatocyte proliferation by combined partial liver resection and thymidine kinase--ganciclovir treatment Pakkanen, T. M., M. Laitinen, et al. (1999), Gene Ther 6(1): 34-41. Abstract: In this study we report an improved method for in vivo gene transfer to liver. Repeated injections of Moloney murine leukemia virus-derived retroviruses containing LDL receptor cDNA were given to the portal vein in combination with a 10% partial liver resection and stimulation of hepatocyte proliferation by plasmid/liposome-mediated thymidine kinase gene transfer and ganciclovir treatment. The method was used for the treatment of LDL receptor deficiency in Watanabe heritable hyperlipidemic rabbits. We demonstrate an increase in hepatocyte proliferation index by thymidine kinase and ganciclovir treatment from 0.9 to 1.35% and a maximum of 35% decrease in total plasma cholesterol level 2-3 months after the gene transfer. A 20% decline was still present after a 52-week follow-up period. A 50% decrease was also observed in plasma triglycerides. Liver function tests indicated a transient increase in plasma alkaline phosphatase level up to 12 weeks after the gene transfer. In situ PCR and RT-PCR analyses indicated that the transgene was present in periportal areas and was transcribed to mRNA 1 week after the gene transfer. Because of the relatively simple and controllable technique we suggest that repeated retrovirus injections via a portal vein catheter together with the limited partial liver resection and plasmid/liposome-mediated thymidine kinase gene transfer-ganciclovir treatment may be used to improve the results of retrovirus-mediated liver gene therapy. |
| Enhanced solubilization and intestinal absorption of cholesterol by oxidized linoleic acid Penumetcha, M., N. Khan-Merchant, et al. (2002), J Lipid Res 43(6): 895-903. Abstract: Solubilization of cholesterol in the intestinal lumen by bile acids and the subsequent formation of mixed micelles is an important step in the absorption of cholesterol. We propose that oxidized fatty acids (ox-FA) may mimic bile acids and form mixed micelles with cholesterol much more efficiently, as compared with unoxidized fatty acids, thereby increasing there absorption. In an in vitro assay at concentrations of 1, 5, and 10 mM, oxidized linoleic acid (ox-18:2) increased the solubilization of cholesterol (3.06, 8.16, and 15.46 nmol/ml) in a dose dependent manner compared with a 10 mM unoxidized linoleic acid (unox-18:2 at 0.97 nmol/ml). The uptake of cholesterol solubilized in the presence of ox-18:2 by Caco-2 cells and everted rat intestinal sacs was greater (1.78 and 1.95 nmol/ml respectively) as compared with the cholesterol solubilized in the presence of unox-18:2 (0.29 and 0.61 nmol/ml; P = 0.05). In addition, when LDL receptor deficient mice were fed a high fat diet along with ox-18:2 their plasma cholesterol levels were greater than animals fed the high fat diet alone (1290 mg/dl vs. 1549 mg/dl, P = 0.013). From these results, we suggest that ox-FA, by enhancing the solubilization of luminal cholesterol, increases the uptake of cholesterol that might lead to hypercholesterolemia and atherosclerosis. |
| Enhanced synthesis and accumulation of proteoglycans in cholesterol-enriched arterial smooth muscle cells Vijayagopal, P. (1993), Biochem J 294 (Pt 2): 603-11. Abstract: To determine the effects of lipid accumulation on proteoglycan synthesis, we studied proteoglycan biosynthesis in rabbit aortic smooth muscle cells in culture. Cholesterol-enrichment was accomplished by incubating confluent smooth muscle cells with cationized low-density lipoprotein. Control and cholesterol-enriched cells were incubated with 35Ssulphate, 3Hglucosamine, or 3Hserine. Metabolically labelled proteoglycans in the cell layer and medium were quantified. During a 20 h incubation period, proteoglycan synthesis in cholesterol-enriched cells increased by 40-50% above that in control cells. A similar increase in precursor incorporation into proteoglycans was also noted following a short 15 min pulse. The cholesterol-enriched cells also showed a 45-50% increase over control rates in the intralysosomal accumulation of a large chondroitin sulphate proteoglycan and a small dermatan sulphate proteoglycan. The enhanced synthesis of proteoglycans in cholesterol-enriched cultures was inhibited by cycloheximide and actinomycin D, which are inhibitors of protein synthesis and transcription respectively. Proteoglycan turnover was investigated by pulse-chase analysis. Following a 2-h pulse, intracellular proteoglycans in cholesterol-enriched cells disappeared, having a half-life of 26.5 h compared with 2.8 h for those in the control cells. The amount of trypsin-releasable proteoglycan was significantly reduced in cholesterol-enriched cells. In addition, the degradation of proteoglycans was severely retarded in cholesterol-enriched cultures. The activities of three acid hydrolases, N-acetyl-beta-hexosaminidase, beta-glucuronidase and cathepsin C, were significantly reduced in cholesterol-enriched cells compared with activities in control cells. The results indicate that proteoglycan metabolism is altered in cholesterol-enriched smooth muscle cells. |
| Enhanced synthesis of epoxyeicosatrienoic acids by cholesterol-fed rabbit aorta Pfister, S. L., J. R. Falck, et al. (1991), Am J Physiol 261(3 Pt 2): H843-52. Abstract: Arachidonic acid metabolism via cyclooxygenase, lipoxygenase, and cytochrome P-450 epoxygenase was investigated in thoracic aortic tissue obtained from rabbits fed either standard rabbit chow or chow containing 2% cholesterol. Aortic strips were incubated with 14Carachidonic acid and A23187. Metabolites from extracted media were resolved by high-pressure liquid chromatography (HPLC). Normal and cholesterol-fed rabbit aortas synthesized prostaglandins (PGs) and hydroxyeicosatetraenoic acids (HETEs). The major cyclooxygenase products were 6-keto-PGF1 alpha and PGE2. Basal aortic 6-keto-PGF1 alpha production was slightly reduced in cholesterol-fed compared with normal rabbits. 12(S)- and 15(S)-HETE were the major aortic lipoxygenase products from both normal and cholesterol-fed rabbits. The structures were confirmed by gas chromatography-mass spectrometry (GC-MS). Only cholesterol-fed rabbit aortas metabolized arachidonic acid via cytochrome P-450 epoxygenase to the epoxyeicosatrienoic acids (EETs). 14,15-, 11,12-, 8,9-, and 5,6-EET were identified based on comigration on HPLC with known 14C-labeled standards and typical mass spectra. Incubation of normal aorta with 14,15-EET decreased the basal synthesis of 6-keto-PGF1 alpha. The other EETs were without effect. The four EET regioisomers relaxed the norepinephrine-precontracted normal and cholesterol-fed rabbit aorta. The relaxation response to 14,15-EET was greater in aortas from cholesterol-fed rabbits. These studies demonstrate that hypercholesterolemia, before the development of atherosclerosis, alters arachidonic acid metabolism via both the cyclooxygenase and epoxygenase pathways. |
| Enhanced vasodilation to acetylcholine in athletes is associated with lower plasma cholesterol Kingwell, B. A., B. Tran, et al. (1996), Am J Physiol 270(6 Pt 2): H2008-13. Abstract: We investigated a change in vascular reactivity as a potential adaptive mechanism to chronic exercise. The study consisted of 2 separate protocols with 10 male athletes and 10 age-matched sedentary male control subjects participating in each. Protocol 1 investigated forearm blood flow responses to intra-arterial infusions of acetylcholine and sodium nitroprusside by use of venous occlusion plethysmography. Protocol 2 used identical techniques to study responses to norepinephrine, angiotensin II (ANG II), and NG-monomethyl-L-arginine (L-NMMA). The percent reduction in forearm vascular resistance to acetylcholine was significantly greater in the athletic compared with the sedentary group (multivariate analysis of variance for repeated measures, P = 0.03). Covariance analysis suggested that the lower total cholesterol level of the athletic group (P = 0.03) may contribute to their enhanced responsiveness to acetylcholine. There were no differences between athletic and sedentary groups in the forearm vascular resistance responses to norepinephrine, ANG II, sodium nitroprusside, or L-NMMA. These data support the hypothesis that long-term endurance training is associated with enhanced endothelium-dependent dilator reserve due to altered lipoprotein levels in athletes. This finding may have therapeutic application in conditions of elevated cholesterol and impaired vasodilator capacity including hypertension, hypercholesterolemia, atherosclerosis, and cardiac failure. |
| Enhancement of aortic cholesterol deposition by dietary linoleic acid in cholesterol-fed mice: an animal model for primary screening of antiatherosclerotic agents Yamaguchi, Y., S. Kitagawa, et al. (1993), J Pharmacol Toxicol Methods 30(3): 169-75. Abstract: We tried to develop an experimental model using mice for the primary screening of antiatherosclerotic agents. Male ICR strain mice were given a high-cholesterol diet supplemented with 10% linoleic acid for 14 weeks. Throughout the experimental period, weight gain of these mice was significantly inhibited as compared to that of control mice given a basal diet, but displayed a steady increase comparable to that of the high-cholesterol diet without linoleic acid. The cholesterol and linoleic acid-fed mice showed increased serum cholesterol and phospholipid levels, and decreased serum triglyceride and high-density lipoprotein-(HDL) cholesterol levels and lecithin/cholesterol acyltransferase (LCAT) activity, as well as a markedly increased lipid peroxide level which was a characteristic appearance in the serum of this mouse model. At the end of the experiment, uniform and significant increases in cholesterol, notably cholesteryl ester, were observed in the aorta. Also found were marked decreases in the aorta contents of desmosine and isodesmosine, which are cross-linking amino acids present only in the elastin. Histological observations showed accumulations of fatty droplets in the intima. These changes were much less in mice receiving a high-cholesterol diet without linoleic acid. In this mouse model, probucol prevented elevation of serum cholesterol, phospholipid, and cholesterol accumulation in the aorta. Increases in lipid peroxide level and decreases in LCAT activity were also prevented. These findings indicate that this mouse model is useful for primary screening of antiatherosclerotic agents with antioxidative activity. |
| Enhancement of fatty acid and cholesterol synthesis accompanied by enhanced biliary but not very-low-density lipoprotein lipid secretion following sustained pravastatin blockade of hydroxymethyl glutaryl coenzyme A reductase in rat liver Carrella, M., L. G. Fong, et al. (1999), Metabolism 48(5): 618-26. Abstract: A 3-week treatment of rats with pravastatin (PV) augmented biliary cholesterol and phospholipid output 3.6- and 2.2-fold over controls, while bile acid (BA) output and kinetics were unchanged. No major changes were detected in hepatic and serum cholesterol concentrations despite the PV inhibitory property on hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase. To evaluate the mechanisms of this adaptive phenomenon, several parameters of hepatic lipid homeostasis were assessed. Biliary cholesterol changes could not be attributed to an increased influx of lipoprotein cholesterol to the liver and bile. Hepatic low-density lipoprotein (LDL) receptor content, as inferred from Western blot analysis, was unchanged, as was the biliary excretion of labeled cholesterol derived from chylomicron remnants. In vivo 3H2O-incorporation studies showed an 80% increase in hepatic cholesterol synthesis, evidence for bypass of the PV block. Remarkably, fatty acid synthesis was also stimulated twofold, providing substrate for hepatic triglycerides, which were slightly enhanced. However, serum triglycerides decreased 52% associated with a 22% decrease in hepatic very-low-density lipoprotein (VLDL) secretion. Thus, the biochemical adaptation following PV treatment produces complex alterations in hepatic lipid metabolism. An enhanced supply of newly synthesized cholesterol and fatty acids in association with a limited VLDL secretion rate augments the biliary lipid secretion pathway in this experimental model. |
| Enhancement of human papillomavirus type 18 gene expression in HeLa cells by 12-O-tetradecanoylphorbol-13-acetate, 3 beta,5 alpha-dihydroxycholestan-6-one, and cholesterol Matsushima, Y., H. Fukasawa, et al. (1994), Biol Pharm Bull 17(9): 1292-5. Abstract: Human papillomavirus type 18 (HPV18) is involved in the genesis of cervical cancer through expression of its viral oncoprotein in infected cells. A tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), was found to increase the level of HPV18 transcripts in an HPV18-harboring cervical cancer cell line, HeLa. A similar increase in HPV18 expression was also observed on treatment of the cells with an oxygenated cholesterol, 3 beta,5 alpha-dihydroxycholestan-6-one (yakkasterone). The effects on HPV18 expression elicited by TPA and yakkasterone were repressed by a protein kinase inhibitor, staurosporine. Treatment of the cells with cholesterol under serum-free conditions also resulted in an apparent increase of HPV18 expression. |
| Enhancement of membrane fluidity in cholesterol-poor endothelial cells pre-treated with simvastatin Morita, I., I. Sato, et al. (1997), Endothelium 5(2): 107-13. Abstract: We examined the membrane fluidity of the cholesterol-poor bovine carotid artery endothelial cells (BAEC). Cholesterol-poor BAEC were obtained by treating the cells with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors under 10% low density lipoprotein (LDL)-deficient serum condition for 2 days. Simvastatin reduced the intracellular cholesterol content significantly at a concentration of 0.1 microgram/ml. The reduction in the cholesterol content was accompanied by the enhancement of the cell membrane fluidity which was measured by a photobleaching technique. Additional data suggested that the reduction in cholesterol content referred to the reduction in the proliferation of BAEC. |