| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Anisotropic motion and molecular dynamics of cholesterol, lanosterol, and ergosterol in lecithin bilayers studied by quasi-elastic neutron scattering Endress, E., H. Heller, et al. (2002), Biochemistry 41(43): 13078-86. Abstract: Quasi-elastic neutron scattering (QENS) was employed to study the molecular dynamics of three structurally related sterols, namely, cholesterol, lanosterol, and ergosterol. Oriented bilayers of dipalmitoylphosphatidylcholine (DPPC) were investigated at 40 mol % sterol content and at three temperatures (20, 36, and 50 degrees C) for two energy resolutions. Data analysis was concentrated on a direct comparison of the out-of-plane and the in-plane high-frequency motions of the three sterols in terms of their rates and amplitudes. The (spatially restricted) diffusive motion of the three sterols in the two directions was characterized by diffusion constants in the range of (5-30) x 10(-12) x m(2) x s(-1), with a significantly faster rate of diffusion along the membrane normal, resulting in a diffusional anisotropy, D(a). At low temperature (20 degrees C), cholesterol showed the highest value (D(a) = 4.5), while lanosterol gave the lowest one (D(a) = 2.0). At high temperature (50 degrees C), ergosterol diffusion had the highest diffusion anisotropy (D(a) = 2.0) compared to lanosterol (D(a) = 1.8) and cholesterol (D(a) = 1.6). Most interestingly, cholesterol showed at all three temperatures an amplitude of its out-of-plane-motion of 1.0-1.1 nm, more than a factor of 3 higher than measured for the other two sterols. This finding suggests that the short alkyl chain of the cholesterol molecule may cross at high frequency the bilayer midplane, while the other two sterols remain confined within the geometrical limits of each monolayer leaflet. The results provide an example of how slight structural alterations of sterols can affect their molecular dynamics in bilayers, which in turn may be relevant to the membrane micromechanical properties. |
| Anisotropic motion of cholesterol in oriented DPPC bilayers studied by quasielastic neutron scattering: the liquid-ordered phase Gliss, C., O. Randel, et al. (1999), Biophys J 77(1): 331-40. Abstract: Quasielastic neutron scattering (QENS) at two energy resolutions (1 and 14 microeV) was employed to study high-frequency cholesterol motion in the liquid ordered phase (lo-phase) of oriented multilayers of dipalmitoylphosphatidylcholine at three temperatures: T = 20 degrees C, T = 36 degrees C, and T = 50 degrees C. We studied two orientations of the bilayer stack with respect to the incident neutron beam. This and the two energy resolutions for each orientation allowed us to determine the cholesterol dynamics parallel to the normal of the membrane stack and in the plane of the membrane separately at two different time scales in the GHz range. We find a surprisingly high, model-independent motional anisotropy of cholesterol within the bilayer. The data analysis using explicit models of molecular motion suggests a superposition of two motions of cholesterol: an out-of-plane diffusion of the molecule parallel to the bilayer normal combined with a locally confined motion within the bilayer plane. The rather high amplitude of the out-of-plane diffusion observed at higher temperatures (T >/= 36 degrees C) strongly suggests that cholesterol can move between the opposite leaflets of the bilayer while it remains predominantly confined within its host monolayer at lower temperatures (T = 20 degrees C). The locally confined in-plane cholesterol motion is dominated by discrete, large-angle rotational jumps of the steroid body rather than a quasicontinous rotational diffusion by small angle jumps. We observe a significant increase of the rotational jump rate between T = 20 degrees C and T = 36 degrees C, whereas a further temperature increase to T = 50 degrees C leaves this rate essentially unchanged. |
| Anitschkow and the cholesterol over-fed rabbit Stehbens, W. E. (1999), Cardiovasc Pathol 8(3): 177-8. |
| Annexin 2-caveolin 1 complex is a target of ezetimibe and regulates intestinal cholesterol transport Smart, E. J., R. A. De Rose, et al. (2004), Proc Natl Acad Sci U S A 101(10): 3450-5. Abstract: Modulation of cholesterol absorption in the intestine, the primary site of dietary cholesterol uptake in humans, can have profound clinical implications. We have undertaken a reverse genetic approach by disrupting putative cholesterol processing genes in zebrafish larvae by using morpholino (MO) antisense oligonucleotides. By using targeted MO injections and immunoprecipitation (IP) experiments coupled with mass spectrometry, we determined that annexin (ANX)2 complexes with caveolin (CAV)1 in the zebrafish and mouse intestine. The complex is heat stable and unaffected by SDS or reducing conditions. MO targeting of anx2b or cav1, which are both strongly expressed in the larval and adult zebrafish intestinal epithelium, prevents formation of the protein heterocomplex. Furthermore, anx2b MO injection prevents processing of a fluorescent cholesterol reporter and results in reduced sterol mass. Pharmacological treatment of mice with ezetimibe disrupts the heterocomplex in only hypercholesterolemic animals. These data suggest that ANX2 and CAV1 are components of an intestinal sterol transport complex. |
| Anomalous enantioselectivity in the sharpless asymmetric dihydroxylation reaction of 24-nor-5beta-cholest-23-ene-3alpha,7alpha,12alpha-triol: synthesis of substrates for studies of cholesterol side-chain oxidation Ertel, N. H., B. Dayal, et al. (1999), Lipids 34(4): 395-405. Abstract: Recently we described a block in bile acid synthesis in cerebrotendinous xanthomatosis (CTX), a lipid storage disease related to an inborn error of bile acid metabolism. In this disease a defect in hepatic microsomal (24S) hydroxylation blocks the transformation of 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol into (24S) 5beta-cholestane-3alpha,7alpha,12alpha,24,25- pentol and cholic acid. Mitochondrial cholesterol 27-hydroxylation has also been reported to be abnormal in CTX subjects, but the relative importance of the enzymatic defect in this alternative microsomal pathway (namely, the 24S hydroxylation of 5beta-cholestane-3alpha,7alpha, 12alpha,25-tetrol relative to the abnormality in mitochondrial 27-hydroxylase) has not been established in CTX. To delineate the sequence of side-chain hydroxylations and the enzymatic block in bile acid synthesis, we synthesized the (23R and 23S) 24-nor-5beta-cholestane-3alpha,7alpha, 12alpha,23,25-pentols utilizing a modified Sharpless asymmetric dihydroxylation reaction on 24-nor-5beta-cholest-23-ene-3alpha, 7alpha, 12alpha-triol, a C26 analog of the naturally occurring C27 bile alcohol, 5beta-cholest-24-ene-3alpha,7alpha,12alpha-triol. Stereospecific conversion of the unsaturated 24-nor triol to the corresponding chiral compounds (23R and 23S), 24-nor-5beta-cholestane-3alpha,7alpha,12alpha,23,25-pentols, was quantitative. However, conversion of the unsaturated 24-nor triol to the chiral nor-pentols had absolute stereochemistry opposite to the products predicted by the Sharpless steric model. The absolute configurations and enantiomeric excess of the C26 nor-pentols and the C27 pentols (synthesized from 5beta-cholest-24-ene-3alpha,7alpha,12alpha-triol for comparison) were confirmed by nuclear magnetic resonance and lanthanide-induced circular dichroism Cotton effect measurements. These results may contribute to a better understanding of the role of the 24S-hydroxylation vs. 27-hydroxylation step in cholic acid biosynthesis. |
| Another cholesterol hypothesis: cholesterol as antioxidant Smith, L. L. (1991), Free Radic Biol Med 11(1): 47-61. Abstract: Current emphasis on cholesterol as agency if not cause of human atherosclerosis and subsequent cardiovascular disease ignores the essentiality of cholesterol in life processes. Additionally ignored is the ubiquitous presence of low levels of oxidized cholesterol derivatives (oxysterols) in human blood and select tissues, oxysterols also implicated in atherosclerosis. Whereas such oxysterols may be regarded putatively as agents injurious to the aorta, an alternative view of some of them is here proposed: that B-ring oxidized oxysterols of human blood represent past interception of blood and tissue oxidants in vivo by cholesterol as an ordinary aspect of oxygen metabolism. Such interception and subsequent efficient hepatic metabolism of oxysterols so formed, with biliary secretion and fecal excretion, constitute as in vivo antioxidant system. Whether cholesterol, oxysterols, oxidized lipoproteins, or oxidants in blood, singly or in concert, cause or exacerbate human atherosclerosis remains to be understood. |
| Another view of cholesterol screening Staines, A. (1990), Pediatrics 86(2): 327-8. |
| Antagonistic effect of the insertion/deletion (HpaI) polymorphism in the regulatory part of the gene for apolipoprotein CI in children with high and low levels of cholesterol Hubacek, J. A., H. Pistulkova, et al. (2004), Cas Lek Cesk 143(2): 94-6. Abstract: BACKGROUND: High plasma lipids are one of the risk factor of atherosclerosis. Both environmental (diet, physic activity) and genetic factors have been implicated in the development of hyperlipidaemia. Apolipoprotein (apo) CI plays an important role in plasma cholesterol and triglycerides transport by VLDL particles. The aim of the study was to establish the role of the insertion/deletion polymorphism in apoCI gene in the determination of plasma lipids in children. METHODS AND RESULTS: Using PCR and restriction analysis (HpaI) we have measured I/D polymorphism in APOCI gene in two groups of children selected from opposite ends of the cholesterol distribution curve of 2000 children. Eighty-two children in high-(HCG) and eighty-six children in low-(LCG) cholesterolemic groups participated on the study. No significant difference was found in the frequencies of the APOCI genotypes or alleles between HCG vs. LCG. Association between LDL cholesterol and genotypes within the LCG was found--the D/D homozygotes have higher lipid level compared to the others (p < 0.05). In LCG opposite, but insignificant (p = 0.09) trend was observed. CONCLUSIONS: The widespread I/D polymorphism in the gene for APOCI determines the plasma lipid levels in childhood and it could become another important genetic marker that plays a role in the genetic determination of cholesterolemia. |
| Anthocyanins increase low-density lipoprotein and plasma cholesterol and do not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits Finne Nielsen, I. L., S. Elbol Rasmussen, et al. (2005), Mol Nutr Food Res 49(4): 301-8. Abstract: Anthocyanin-rich beverages have shown beneficial effects on coronary heart disease in epidemiological and intervention studies. In the present study, we investigated the effect of black currant anthocyanins on atherosclerosis. Watanabe Heritable Hyperlipidemic rabbits (n = 61) were fed either a purified anthocyanin fraction from black currants, a black currant juice, probucol or control diet for 16 weeks. Purified anthocyanins significantly increased plasma cholesterol and low-density lipoprotein (LDL) cholesterol. Intake of black currant juice had no effect on total plasma cholesterol, but lowered very-low-density lipoprotein (VLDL) cholesterol significantly. There were no significant effects of either purified anthocyanins or black currant juice on aortic cholesterol or development of atherosclerosis after 16 weeks. Probucol had no effect on plasma cholesterol but significantly lowered VLDL-cholesterol and decreased aortic cholesterol accumulation. The erythrocyte antioxidant enzyme glutathione peroxidase was significantly increased by purified anthocyanins and superoxide dismutase was increased by both anthocyanin-containing treatments. Other markers of plasma antioxidant capacity, antioxidant enzymes, protein and lipid oxidation were not affected by any of the anthocyanin treatments. Adverse effects of purified anthocyanins were observed on plasma- and LDL-cholesterol. These effects were not observed with black currant juice, suggesting that black currants may contain components reducing the adverse effects of anthocyanins. |
| Anthropometric and dietary determinants of blood levels of HDL cholesterol in a population-based study. The REGICOR study. Researchers of the REGICOR study Senti, M., R. Masia, et al. (1998), Rev Esp Cardiol 51(12): 979-87. Abstract: OBJECTIVES: The aim of the present study was to identify dietary and anthropometric factors influencing HDL cholesterol levels in the region of Girona. POBLATION AND METHODS: A cross-sectional study was designed with random recruitment and 798 men and 862 women were included. Anthropometric variables were collected, the energy expenditure in physical activity was calculated and a dietary questionnaire was supplied in order to obtain nutritional data. Furthermore, lipid levels and lipoprotein concentrations were determined. RESULTS: Significant differences were found in serum triglycerides, body mass index, glucose levels and alcohol intake between the upper and the lower tertils of HDL cholesterol in both men and women. In men, energy expenditure in physical activity was significantly associated with HDL cholesterol levels, as well as total fat and monounsaturated fat. In women, together with the waist-to-hip ratio and fasted glycemia, vitamin C was the dietary factor positively associated with HDL cholesterol levels. CONCLUSIONS: Moderate alcohol intake, physical activity, vitamin C consumption and optimizing body weight strongly contribute to increased HDL cholesterol levels in our region. |
| Antiatherogenic effect of angiotensin converting enzyme inhibitor (benazepril) and angiotensin II receptor antagonist (valsartan) in the cholesterol-fed rabbits Li, J., N. Hirose, et al. (1999), Atherosclerosis 143(2): 315-26. Abstract: The purpose of this study was to determine whether an angiotensin converting enzyme (ACE) inhibitor, benazepril, and an angiotensin receptor antagonist, valsartan, would decrease atherosclerotic severity in cholesterol-fed rabbits. Male rabbits were fed either: (a) normal rabbit chow; (b) 2% cholesterol diet; (c) 2% cholesterol diet supplemented by benazepril (3 mg/kg per day, subcutaneous injection); or (d) 2% cholesterol diet supplemented by valsartan (1 mg/kg per day, subcutaneous injection). After 12 weeks, the arteries were harvested for histomorphometry and immunohistochemistry. We observed that decreases in serum triglyceride (TG) and total cholesterol (TC) and ACE activity with benazepril-treatment were more than 60, 30, and 84%, respectively, in comparison with the cholesterol group; with valsartan-treatment, TG levels were 53% lower than in the cholesterol group, however, there was no significant difference in TC and ACE activity. The percentage of aortic surface atherosclerotic area, intimal thickness and the ratio of aortic intimal area to medial area were about 40% lower in the benazepril-treated group in comparison with those of the cholesterol group; the difference was more than 60% in the thoracic aorta. The valsartan-treated group had 23% less atherosclerotic area, less effective than benazepril treatment. The percent of PCNA-positive cells and the number of intimal proliferative cells/mm2 were significantly less in the benazepril-treated group compared with the cholesterol group (by 55 and 63%); these parameters were 35 and 17% lower, respectively, with valsartan. The ratio of proliferating macrophages to smooth muscle cells (SMCs) was 3:1 in the cholesterol group, 1:1 in the benazepril and 2:1 in the valsartan-treated group. These results indicate that benazepril could reduce atherosclerotic progression by decreasing macrophage proliferation and accumulation in the arterial wall. The mechanisms for reducing atherosclerotic progression by benazepril and valsartan may be related to reduction of TG and blockade of the angiotensin II action. |
| Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits Lee, C. H., T. S. Jeong, et al. (2001), Biochem Biophys Res Commun 284(3): 681-8. Abstract: The anti-atherogenic effects of the citrus flavonoids, naringin and naringenin, were evaluated in high cholesterol-fed rabbits. At 3 months of age, 30 male New Zealand White (NZW) rabbits were divided into three groups (n = 10 per group). The rabbits were fed a 1% cholesterol diet alone (control group) or a diet supplemented with either 0.1% naringin or 0.05% naringenin for 8 weeks. The plasma lipoprotein levels, total cholesterol, triglyceride, and high-density lipoprotein showed no significant differences in the control and experimental groups. Hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity was slightly low in naringin (5.0%)- and naringenin (15.0%)-fed rabbits, compared to control group. The aortic fatty streak areas were significantly lower in both the naringin (19.2 +/- 5.6%)- and naringenin (18.1 +/- 6.5%)-supplemented groups than in the control group (60.4 +/- 14.0%). The expression levels of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1), by semiquantitative RT-PCR analysis of the thoracic aorta, were significantly lower in the flavonoids supplemented groups than in the control group. These results suggest that the anti-atherogenic effect of the citrus flavonoids, naringin and naringenin, is involved with a decreased hepatic ACAT activity and with the downregulation of VCAM-1 and MCP-1 gene expression. |
| Antiatherogenic effect of estrogen abolished by balloon catheter injury in cholesterol-clamped rabbits Holm, P., S. Stender, et al. (1997), Arterioscler Thromb Vasc Biol 17(8): 1504-11. Abstract: The purpose of this study was to investigate the importance of an intact endothelial cell layer for the direct antiatherogenic effect of estrogen on the arterial wall. Thirty rabbits were bilaterally ovariectomized and subjected to mechanical injury of the endothelium by balloon catheterization of the upper thoracic aorta. Immediately after the operation, treatment was initiated with either 17 beta-estradiol or placebo given intramuscularly. All rabbits were clamped at a similar plasma cholesterol level from 1 week before the operation until the experiment was terminated 13 weeks later. In the undamaged aorta, ie, the aortic arch, the lower thoracic aorta, and the upper abdominal aorta, the estrogen-treated rabbits had one third (P =.06), one sixth (P =.002), and one seventh (P =.001), respectively, the accumulation of cholesterol of the placebo-treated rabbits. In the upper thoracic aorta that had been subjected to mechanical injury of the endothelium, however, aortic cholesterol accumulation was not significantly different between the two groups. Similar results were obtained by histological evaluation of the aortic tissues. Immunohistochemical staining with antibodies against macrophages, smooth muscle cells, and T lymphocytes revealed no significant differences in the intimal distribution of cells between estrogen- and placebo-treated rabbits, except for a higher number of T lymphocytes per unit intimal area of the undamaged aortic arch (P <.0005) in the estrogen-treated-rabbits than the placebo-treated rabbits. This is the first study to demonstrate that the antiatherogenic effect of estrogen is abolished by balloon catheter injury in cholesterol-clamped rabbits. These results may indicate that an intact endothelial cell layer is crucial for the direct antiatherogenic effect of estrogen on the arterial wall. |
| Anti-atherogenic effect of NIP-200 on the experimental atherosclerosis in cholesterol-fed rabbits Sakashita, M., S. Nakayama, et al. (1992), Nippon Yakurigaku Zasshi 99(1): 37-43. Abstract: The anti-atherogenic effect of NIP-200 3,5-dimethyl-4,6-diphenyl-tetrahydro-2H-1,3,5-thiadiazine-2-thione) was studied in experimental models of 1% cholesterol diet (HCD)-fed rabbits. Interference with growth of the animals did not occur in NIP-200-treated rabbits. NIP-200 had no effect on plasma total cholesterol (TC), triglyceride, free cholesterol and phospholipid during the entire experimental period. However, NIP-200 increased high density lipoprotein-cholesterol (HDL-C) at 1, 2, 4 and 6 weeks, although the average rate of increase was not statistically significant. Percentage surface areas of atherosclerotic lesions on the aorta in NIP-200-treated rabbits (26 +/- 6%) was significantly lower than those in HCD-fed rabbits (48 +/- 8%) (P less than 0.05). Histological studies indicated that NIP-200 prevented intimal thickening, proliferation of elastic fibers and fatty necrosis. Thus, NIP-200 prevented the progression of atherosclerosis without affecting the serum TC. The above results suggest that the improvement of lipoprotein metabolism on the arterial wall and the prevention of migration and proliferation of arterial smooth muscle cells may also be important factors in the progression of atherosclerosis. |
| Antiatherogenic effects of 17 beta-estradiol and 17 alpha-estradiol and its derivative J811 in cholesterol-fed rabbits with thyroid inhibition Buko, V. U., O. Lukivskaya, et al. (2001), Climacteric 4(1): 49-57. Abstract: OBJECTIVE: The aim of this study was to investigate the antiatherogenic effects of 17 beta-estradiol and 17 alpha-estradiol and its derivative J811 (estra-1,3,5(10),8-tetraene-3, 17 alpha-diol), having a non-feminizing effect and high antioxidant potential, in male rabbits. EXPERIMENTAL DESIGN: Male White-Russian rabbits weighing 2.1-2.6 kg were fed either a standard or a high-cholesterol (200 mg/kg) diet, with thyroid function-inhibiting thiouracil (20 mg/kg) combined with cholic acid (40 mg/kg) administered daily in sunflower oil for 3 months. During the last month of the study, estrogens were administered by gavage at a dose of 0.02 or 0.1 mg/kg. RESULTS AND CONCLUSIONS: All three estrogens exerted remarkable antiatherosclerotic effects. Decreases in serum and aortic-wall lipid parameters and the index of atherogenicity were dependent on estrogen dose. Morphological evaluation of the aortic wall (height of plaques, size of plaque relative to aortic half-circumference) showed only weak therapeutic effects with all three estrogens. It is an open question whether the treatment period was too short to reverse the above changes. On the other hand, the data clearly suggest that 17 alpha-estradiol and J811 offer new perspectives for the prevention of atherosclerosis in men, which is similar to that found with 17 beta-estradiol in women. |
| Antiatherogenic effects of a novel lipoprotein lipase-enhancing agent in cholesterol-fed New Zealand white rabbits Chiba, T., S. Miura, et al. (1997), Arterioscler Thromb Vasc Biol 17(11): 2601-8. Abstract: Following our report that administration of 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl) benzamide (NO-1886) to rats elevated postheparin lipoprotein lipase (LPL) activity through an increase in the enzyme mass, we now investigate antiatherogenic effects of NO-1886 in cholesterol-fed New Zealand White rabbits. For 20 weeks, four groups of male rabbits received regular rabbit chow (the normal control), 0.25% cholesterol-containing chow (the control), and cholesterol chow supplemented with 0.5% and 1.0% NO-1886, respectively. Postheparin LPL activity at week 10 was raised by 30% in 0.5% of the NO-1886 group and 40% in 1.0% of the NO-1886 group compared with those in the control. The area under the curve of plasma cholesterol level was not different in three cholesterol-fed groups whereas the area under the curve of HDL cholesterol was approximately twofold greater in the two NO-1886 groups than in the control, and the area under the curve of plasma triglyceride was reduced to the level of the normal control. LPL activity was correlated with HDL cholesterol (r =.764, n = 18) and triglyceride (r = -.627, n = 18). Relative atheromatous area, aortic cholesterol, and triglyceride contents were reduced to approximately 25%, 60%, and 55%, respectively, of the control values by NO-1886 ingestion. Multiple regression analysis of LPL, HDL cholesterol, and triglyceride indicated that HDL cholesterol was the most powerful protector against aortic cholesterol accumulation, and triglyceride was the one to protect against the atheromatous area. We concluded that NO-1886 prevented the development of atherosclerosis through increasing LPL activity with a consequent increase in HDL cholesterol and a decrease in triglyceride without a significant influence of plasma cholesterol level. |
| Anti-atherogenic effects of cholesterol vaccination Bailey, J. M., R. Bright, et al. (1994), Biochem Soc Trans 22(4): 433S. |
| Anti-atherogenic effects of the acyl-CoA:cholesterol acyltransferase inhibitor, avasimibe (CI-1011), in cultured primary human macrophages Rodriguez, A. and D. C. Usher (2002), Atherosclerosis 161(1): 45-54. Abstract: Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce atherosclerotic lesions in animals; however, the mechanism(s) for this effect remains unclear. Therefore, we used cultured primary human monocyte-derived macrophages (HMMs) to examine the effect of the ACAT inhibitor, avasimibe (CI-1011), during foam cell formation and during cholesterol efflux from established foam cells. To examine the effect of CI-1011 on foam cell development, HMMs were incubated with aggregated acetylated LDL (ag-acLDL)+/-CI-1011 for 48 h. Total cholesterol (TC) was 29% lower in HMMs incubated with ag-acLDL and CI-1011 compared with ag-acLDL (P<0.05). To determine if TC reduction was due to reduced ag-acLDL uptake by CI-1011, 125I-acLDL binding at 4 degrees C for 4 h to HMMs preincubated with acLDL or ag-acLDL, CI-1011, acLDL+CI-1011, or ag-acLDL+CI-1011 for 48 h was measured. Specific binding was 40% lower in cells preincubated with acLDL+CI-1011, 52% lower in cells preincubated with ag-acLDL+CI-1011 and 49% lower in cells preincubated with CI-1011 compared with cells preincubated with acLDL (P<0.0003). Because CI-1011 appeared to directly affect acLDL binding, 125I-acLDL (3-80 microg protein/ml) binding was done in HMMs preincubated with CI-1011 (0-10 microg/ml) for 48 h. The calculated B(max) decreased in HMMs exposed to increasing concentrations of CI-1011, suggesting that CI-1011 altered scavenger receptor function and/or number. To examine the effects of CI-1011 on cholesterol efflux from established foam cells, we first examined whether CI-1011 was cytotoxic. HMMs were preincubated with ag-acLDL for 24 h, and then radiolabeled with 14Cadenine for 2 h (time zero). The radiolabeled cells were exposed to control RPMI medium or the same medium+HDL, CI-1011, or HDL+CI-1011 for 24 h. The release of 14Cadenine into the medium was not significantly different between cells exposed to RPMI, HDL, CI-1011, or HDL+CI-1011, suggesting that CI-1011 was not cytotoxic. Foam cells exposed to RPMI and CI-1011 (1-10 microg/ml) for 48 h showed time dependent reduction in cellular TC mass, with a corresponding increase in radiolabeled unesterified cholesterol into the medium. We then asked whether CI-1011 enhanced apoE mediated cholesterol efflux. Although cellular apoE increased between 2- and 7-fold in foam cells compared to control macrophages, apoE secreted into the medium was not significantly different between cells exposed to RPMI or CI-1011. Thus, CI-1011 exerted anti-atherogenic effects by reducing TC accumulation, inhibiting acLDL binding, and by limiting lipid storage in HMMs. |
| Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation Bocan, T. M., M. J. Mazur, et al. (1994), Atherosclerosis 111(1): 127-42. Abstract: Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect. |
| Anti-atherosclerotic activity of the calcium antagonist lacidipine in cholesterol-fed hamsters Cristofori, P., A. Lanzoni, et al. (2000), Biomed Pharmacother 54(2): 93-9. Abstract: We have investigated the activity of the calcium antagonist lacidipine in male hamsters fed an atherogenic diet containing 2% cholesterol and 5% butter. Animals were examined at 14, 20 and 24 weeks of treatment. At 14 weeks, in hamsters fed the atherogenic diet and without lacidipine treatment, there were significant increases in serum levels of total cholesterol, triglycerides and lipoproteins; these values were approximately similar at week 24. Lacidipine treatment at 0.3, 1.0 and 3.0 mg/kg/d did not affect levels of serum cholesterol, triglycerides and lipoproteins. At 24 weeks, in hyperlipidemic hamsters fed the atherogenic diet, the area of the fatty streak in the aortic arch covered a mean area of 375 +/- 145 micron2 x 100, which accounted for 2.7% of the total surface area of the aortic arch. In hamsters fed the atherogenic diet and treated with lacidipine at 0.3, 1.0 and 3.0 mg/kg, at 24 weeks, the surface area of the aortic arch lesion was significantly reduced by 41 to 71%. In the thoracic aorta at 24 weeks, in lacidipine-treated animals, both the incidence and degree of severity of the lesions was reduced, the area of the fatty streak being lowered by 78 to 97% in comparison with non-lacidipine-treated control animals. Ultrastructural examination demonstrated that the early changes in the aorta in hamsters fed the atherogenic diet involved the intima and smooth muscle cells; lacidipine treatment reduced the severity of the intimal lesions significantly. With SEM, lacidipine administration was seen to reduce endothelial irregularity and the presence of crater-like lesions. At TEM, treatment with lacidipine reduced the number of foam cells and the presence of liposomes in the subendothelium. This investigation demonstrates that in the hyperlipidemic hamster, lacidipine treatment decreases atheromatous lesions without lowering serum lipids. It is suggested that lacidipine influences the atherogenic process by an unusual mechanism which may be related to a combination of both the long-lasting calcium antagonism of the drug and significant antioxidant activity. |