| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Interactions of serum copper, selenium, and low density lipoprotein cholesterol in atherogenesis Salonen, J. T., R. Salonen, et al. (1991), Bmj 302(6779): 756-60. Abstract: OBJECTIVE--To investigate the interactions between serum copper, selenium, and low density lipoprotein cholesterol concentrations with regard to the progression of carotid atherosclerosis. DESIGN--Longitudinal study of a cohort of middle aged men followed up for 24 months. SETTING--Epidemiological survey of the population of seven communities in eastern Finland. SUBJECTS--126 men aged 42, 48, 54, or 60 at examination randomly selected from a population based sample of 2682 men. MAIN OUTCOME MEASURES--Increase in maximal carotid intima media thickness. RESULTS--The mean increase in the maximal common carotid intima media thickness after two years was greater in men with high serum copper concentrations (0.16 mm compared with 0.08 mm in men with concentrations less than 17.6 mumol/l; p = 0.010), those with low serum selenium concentrations (0.15 mm compared with 0.09 mm in men with concentrations greater than or equal to 1.40 mumol/l; p = 0.035), and those with raised serum low density lipoprotein cholesterol concentrations (0.15 mm compared with 0.08 mm in men with concentrations less than 4.0 mmol/l; p = 0.032) after adjustment for age and cigarette pack years in a three way analysis of covariance. A raised serum low density lipoprotein concentration was associated with accelerated progression of atherosclerosis only in men with higher than median serum copper concentrations (net difference 0.22 mm; p less than 0.001 for two way interaction), and this synergism was even more pronounced in men with serum selenium concentrations below the median value (net difference 0.41 mm; p = 0.042 for three way interaction). CONCLUSION--These data provide evidence of a synergistic effect of copper (a pro-oxidant), a low serum concentration of selenium (a cofactor of an enzyme that scavenges free radicals), and low density lipoprotein cholesterol concentration in atherogenesis. |
| Interactive effect of hesperidin and vitamin E supplements on cholesterol metabolism in high cholesterol-fed rats Park, Y. B., K. M. Do, et al. (2001), Int J Vitam Nutr Res 71(1): 36-44. Abstract: Certain bioflavonoids are potent antioxidants and have pharmacologic effects similar to those of vitamin E. Accordingly, the interactive effect of hesperidin and vitamin E was studied with respect to cholesterol metabolism and the antioxidant status. Hesperidin supplement (0.1%, wt/wt) with comparable levels of vitamin E was provided with a high-cholesterol (1%, wt/wt) diet to rats for 5 weeks. The amount of vitamin E included in the hesperidin-free and hesperidin diets was either a low (low-E) or a normal (normal-E) level. The hesperidin supplement and different levels of dietary vitamin E did not significantly alter the concentrations of plasma triglycerides. However, the inclusion of hesperidin significantly lowered the concentration of plasma cholesterol in both the low-vitamin E group and the normal-vitamin E group compared to the hesperidin-free groups (p < 0.05). The hepatic triglyceride content was significantly lowered by the hesperidin supplement, as opposed to the plasma triglyceride content, regardless of the vitamin E level in the diet. The hepatic HMG-CoA reductase activity was significantly lowered by the hesperidin supplement with both the low-vitamin E and the normal-vitamin E compared to the hesperidin-free groups (p < 0.05). The hepatic HMG-CoA reductase activity was also significantly lowered with an increase in the dietary vitamin E within the hesperidin and hesperidin-free groups. The excretion of fecal neutral sterol and acidic sterols tended to be lower with the hesperidin supplement. Neither dietary hesperidin nor vitamin E significantly changed the hepatic antioxidant enzyme activity. This data indicates that hesperidin lowers the concentration of plasma cholesterol and the hepatic triglyceride content regardless of the dietary vitamin E level. However, the concentration of plasma cholesterol in the hesperidin-free groups was dependent on the dietary vitamin E level. This information may contribute to understanding the interactive effect of hesperidin and vitamin E on cholesterol biosynthesis in high cholesterol-fed rats. |
| Interactive effects of dietary cholesterol and different saturated fatty acids on lipoprotein metabolism in the hamster Billett, M. A., J. S. Bruce, et al. (2000), Br J Nutr 84(4): 439-47. Abstract: The present study examines the interactive effects of three fatty acids: myristic, palmitic and stearic acids, with dietary cholesterol, on lipoprotein metabolism in the hamster. Each saturated fatty acid was fed at a concentration of 100 g pure synthetic triacylglycerol/kg in the presence of 100 g triolein/kg and was fed in the presence of 0.05, 1.2 or 2.4 g dietary cholesterol/kg. Dietary cholesterol increased the concentration of cholesterol in each of the major plasma lipoprotein fractions. The largest effects on VLDL and LDL were seen in the presence of tripalmitin where the increase between the lowest and highest dietary cholesterol groups were 129% and 38% respectively. In contrast, HDL showed the greatest change in the tristearin group when the equivalent increase was 59%. No interactive effects of dietary cholesterol and fat were seen on hepatic mRNA concentrations for the LDL receptor, hydroxymethylglutaryl-CoA reductase or the microsomal triacylglycerol transfer protein. As the amount of cholesterol in the diet increased, large differences were seen in the storage of hepatic cholesterol ester. At the highest dietary cholesterol intake the amount of hepatic cholesterol ester was 1.7-fold higher in the animals fed trimyristin compared with those fed tripalmitin. These results suggest that, as the amount of cholesterol in the diet is increased, palmitic acid becomes more hypercholesterolaemic. This is associated with a reduced ability to store cholesterol ester in the liver. |
| Interactive effects of dietary cholesterol and saturated fat on low density lipoprotein cholesterol Salter, A. M., J. S. Bruce, et al. (1996), Biochem Soc Trans 24(2): 180S. |
| Interactive effects of increased intake of saturated fat and cholesterol on atherosclerosis in the Japanese quail (Coturnix japonica) Yuan, Y. V., D. D. Kitts, et al. (1998), Br J Nutr 80(1): 89-100. Abstract: Increasing the energy value of diets with dietary fat, particularly fats rich in saturated fatty acids, can result in the elevation of plasma total and lipoprotein cholesterol. In the present study, experimental diets were designed to examine the effects of increasing the energy content of diets with a saturated fat source and cholesterol in a non-purified diet on hyperlipoproteinaemia and aortic plaque composition in the atherosclerosis-susceptible Japanese quail (Coturnix japonica) model of human atherosclerosis. Commercial poultry diets containing two levels (i.e. 60 or 120 g/kg) of beef tallow as the primary source of saturated fat were balanced for endogenous cholesterol or supplemented with cholesterol (i.e. 0.5 or 5.0 g/kg) and fed to quail for 9 weeks to examine the effects on whole plasma, lipoprotein and aortic plaque lipid composition in relation to aortic plaque formation. Hypercholesterolaemia (P < 0.001) was confirmed in birds fed on high-cholesterol (HC) diets only. An interaction (P = 0.05) between dietary cholesterol and fat intake level was observed for plasma triacylglycerols (TG) and was specific to changes observed in VLDL composition. Diet-induced changes in lipoprotein total cholesterol, TG and phospholipid composition were greatest in the portomicron and VLDL fractions in birds fed on atherogenic diets. Hyperlipoproteinaemia induced by the 60 g/kg added beef tallow-HC diet resulted in significant (P < 0.001) aortic plaque deposition, which was further enhanced in birds fed on the 120 g/kg beef tallow-HC diet. Quail fed on 120 g/kg beef tallow-HC diets exhibited the most severe aortic plaque formation, with marked increases in aortic tissue cholesterol content and quantifiable amounts of several cholesterol oxides (5,6 alpha-epoxy-5 alpha-cholesterol, 7 beta-hydroxycholesterol, cholestanetriol, 7-ketocholesterol and 25-hydroxycholesterol). In summary, hyperlipoproteinaemia associated with HC diets with a greater proportion of energy from saturated fat produced a combined effect in altering plasma and lipoprotein lipid composition as well as aortic tissue cholesterol and cholesterol oxide content in the Japanese quail. |
| Interbilayer interactions between sphingomyelin and sphingomyelin/cholesterol bilayers McIntosh, T. J., S. A. Simon, et al. (1992), Biochemistry 31(7): 2020-4. Abstract: Pressure versus fluid spacing relations have been obtained for sphingomyelin bilayers in the gel phase and equimolar sphingomyelin/cholesterol in the liquid-crystalline phase by the use of X-ray diffraction analysis of osmotically stressed aqueous dispersions and oriented multilayers. For interbilayer separations in the range of 5-20 A, the repulsive hydration pressure decays exponentially with increasing fluid spacing. The decay length (lambda) of this repulsive pressure is about 2 A for both bovine brain and N-tetracosanoylsphingomyelin, similar to that previously found for phosphatidylcholine bilayers. However, both the magnitude of the hydration pressure and the magnitude of the dipole potential (V) measured for monolayers in equilibrium with liposomes are considerably smaller for sphingomyelin than for either gel or liquid-crystalline phosphatidylcholine bilayers. Addition of equimolar cholesterol increases both the magnitude of the hydration pressure and the dipole potential. These data suggest that the magnitude of the hydration pressure depends on the electric field at the interface as given by (V/lambda)2. For sphingomyelin bilayers, there is a sharp upward break in the pressure-fluid spacing relation at an interbilayer spacing of about 5 A, indicating the onset of steric hindrance between the head groups of apposing bilayers. |
| Intercalation of small hydrophobic molecules in lipid bilayers containing cholesterol Worcester, D. L., K. Hamacher, et al. (1996), Basic Life Sci 64: 215-26. Abstract: Partitioning of small hydrophobic molecules into lipid bilayers containing cholesterol has been studied using the 2XC diffractometer at the University of Missouri Research Reactor. Locations of the compounds were determined by Fourier difference methods with data from both deuterated and undeuterated compounds introduced into the bilayers from the vapor phase. Data fitting procedures were developed for determining how well the compounds were localized. The compounds were found to be localized in a narrow region at the center of the hydrophobic layer, between the two halves of the bilayer. The structures are therefore intercalated structures with the long axis of the molecules in the plane of the bilayer. |
| Interdigestive gallbladder emptying, antroduodenal motility, and motilin release patterns are altered in cholesterol gallstone patients Stolk, M. F., K. J. Van Erpecum, et al. (2001), Dig Dis Sci 46(6): 1328-34. Abstract: The role of interdigestive gallbladder emptying in gallstone formation is unknown. In fasting healthy subjects, gallbladder emptying is associated with antral phase III of the migrating motor complex (MMC) and high plasma motilin. Therefore, gallbladder volumes and motilin levels were measured during 13 MMC cycles in 10 cholesterol gallstone patients and compared with 20 MMC cycles in 10 healthy subjects. MMC cycle length was longer in gallstone patients than in healthy subjects (158.2 +/- 17.0 vs 105.5 +/- 10.4 min, respectively; P < 0.05), due to longer phase I (39.8 +/- 5.7 vs 17.2 +/- 3.7 min, respectively; P < 0.05). In contrast to healthy subjects, gallstone patients had no significant fluctuations of gallbladder volume during the MMC cycle, and motilin concentrations were not different in MMC cycles with phase III originating in antrum or duodenum. During MMC cycles with phase III originating in the duodenum, motilin levels were twice as high in gallstone patients as in healthy subjects (P < 0.002). In conclusion, cholesterol gallstone patients have an abnormal MMC and motilin release pattern. Their interdigestive gallbladder emptying is reduced and dissociated from the MMC. These disturbances may contribute to gallstone formation. |
| Interfacial exclusion pressure determines the ability of apolipoprotein A-IV truncation mutants to activate cholesterol ester transfer protein Weinberg, R. B., R. A. Anderson, et al. (2002), J Biol Chem 277(24): 21549-53. Abstract: We used a panel of recombinant human apolipoprotein (apo) A-IV truncation mutants, in which pairs of 22-mer alpha-helices were sequentially deleted along the primary sequence, to examine the impact of protein structure and interfacial activity on the ability of apoA-IV to activate cholesterol ester transfer protein. Circular dichroism and fluorescence spectroscopy revealed that the secondary structure, conformation, and molecular stability of recombinant human apoA-IV were identical to the native protein. However, deletion of any of the alpha-helical domains in apoA-IV disrupted its tertiary structure and impaired its molecular stability. Surprisingly, determination of the water/phospholipid interfacial exclusion pressure of the apoA-IV truncation mutants revealed that, for most, deletion of amphipathic alpha-helical domains increased their affinity for phospholipid monolayers. All of the truncation mutants activated the transfer of fluorescent-labeled cholesterol esters between high and low density lipoproteins at a rate higher than native apoA-IV. There was a strong positive correlation (r = 0.790, p = 0.002) between the rate constant for cholesterol ester transfer and interfacial exclusion pressure. We conclude that molecular interfacial exclusion pressure, rather than specific helical domains, determines the degree to which apoA-IV, and likely other apolipoproteins, facilitate cholesterol ester transfer protein-mediated lipid exchange. |
| Interfacial tension of phosphatidylcholine-cholesterol system in monolayers at the air/water interface Brzozowska, I. and Z. A. Figaszewski (2002), Biophys Chem 95(2): 173-9. Abstract: Interfacial tension of an egg lecithin-cholesterol system was measured across the whole concentration range. Surface pressure-area isotherm measurements were carried out in a Langmuir trough at the air/water interface at room temperature (22 degrees C). The interfacial tension of the air/water interface was divided into contributions of components. The interfacial tension of a 1:1 complex between phosphatidylcholine and cholesterol was calculated. Its value equals 18 mN/m. The difference between the stability constant of 1:1 complex in the bilayer and the monolayer at the air/water interface is discussed. |
| Interfacial thickness of liposomes containing poly(ethylene glycol)-cholesterol from electrophoresis Janzen, J., X. Song, et al. (1996), Biophys J 70(1): 313-20. Abstract: The electrophoretic mobilities of liposomes incorporating a polyethylene glycol (PEG) headgroup coupled to cholesterol for PEG of average chain index 3.0, 13.2, and 22.3 have been determined as a function of PEG-cholesterol mole fraction between 5% and 40% and ionic strength between 2 and 200 mM. The liposome compositions were 40 mole % cholesterol plus PEG-cholesterol, 10 mole % 1,2-dipalmitoyl-sn-glyerco-3-phosphoglycerol, and 50 mole % egg phosphatidylcholine. The mobilities were fit to a model in which the PEG forms a surface layer of polymer subject to viscous drag arising from electroosmotic flow within this layer. The model provides estimates of the average layer thickness that are comparable to those determined from contemporary models of surface-attached polymer. |
| Interferon-beta treatment decreases cholesterol plasma levels in multiple sclerosis patients Morra, V. B., G. Coppola, et al. (2004), Neurology 62(5): 829-30. |
| Interferon-gamma impedes reverse cholesterol transport and promotes foam cell transformation in THP-1 human monocytes/macrophages Reiss, A. B., C. A. Patel, et al. (2004), Med Sci Monit 10(11): BR420-5. Abstract: BACKGROUND: Cholesterol 27-hydroxylase, an enzyme expressed at high levels by human monocytes/macrophages, provides a first line of defense against the development of atherosclerosis. Prior studies have suggested that the cytokine interferon-gamma (IFN-gamma) promotes atherosclerosis. We therefore examined the effect of IFN-g on macrophage foam cell formation and on expression of the anti-atherogenic 27-hydroxylase in THP-1 human monocytes/macrophages. MATERIAL/METHODS: THP-1 monocytes and acetylated LDL-treated THP-1 macrophages were incubated in the presence or absence of IFN-gamma (500 U/ml) with or without the addition of IFN- gamma receptor blocking or neutralizing antibody. Foam cell formation was quantified based on percentage of macrophages harboring oil red O-stained globules. Cellular mRNA and protein were isolated. 27-Hydroxylase message was measured by RT-PCR and 27-hydroxylase protein by immunoblot. RESULTS: IFN-gamma -treated THP-1 macrophages exhibit increased foam cell transformation compared to untreated cells under cholesterol loading conditions. IFN-gamma-promoted foam cell formation is abolished by pre-treatment with either IFN-gamma neutralizing or IFN-gamma receptor blocking antibody. IFN-gamma diminishes cholesterol 27-hydroxylase expression in THP-1, and this IFN-gamma -induced downregulation is prevented by pre-treating the cultured cells with either IFN-gamma neutralizing or IFN-gamma receptor blocking antibody. CONCLUSIONS: Imbalances in cellular cholesterol flux within macrophages lead to formation of lipid-laden foam cells, a critical step in the pathogenesis of atherosclerosis. We have demonstrated that IFN-gamma, acting through the IFN-gamma receptor, decreases expression of 27-hydroxylase and increases propensity to foam cell formation in the cell line THP-1. These observations suggest that one mechanism by which IFN-g promotes atherosclerosis may involve affecting expression of cholesterol 27-hydroxylase, a cholesterol homeostatic protein. |
| Interferon-gamma-mediated downregulation of cholesterol efflux and ABC1 expression is by the Stat1 pathway Wang, X. Q., C. G. Panousis, et al. (2002), Arterioscler Thromb Vasc Biol 22(5): e5-9. Abstract: The pathological role of interferon-gamma (IFN-gamma) in atherosclerosis is mediated through effects on macrophages, foam cells, and other vascular cells. Recently, we reported that ATP-binding cassette transporter 1(ABC1) message and protein levels were decreased 3- to 4-fold in foam cells by IFN-gamma. In the present study, the pathway by which IFN-gamma inhibited ABC1 expression was investigated with signal transducers and activators of transcription (Stat1) knockout mice. IFN-gamma-stimulated, wild-type, macrophage-derived foam cells, as previously reported, exhibited a decrease in cholesterol efflux and ABC1 expression as well as an increase in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, IFN-gamma treatment of foam cells from Stat1 knockout mice failed to demonstrate reductions in efflux or ABC1 expression at the message or protein levels, nor were there any increases in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, ABC1 mRNA expression in macrophages from Stat1 knockout mice could still be demonstrated to be increased by lipid loading with acetylated low density lipoprotein. Finally, Stat1-independent gene activation by IFN-gamma was intact in the Stat1 KO macrophages, inasmuch as IFN-gamma was shown to stimulate increases in interleukin-6 production in the Stat1 KO macrophages that were comparable to those observed in the wild-type macrophages. Therefore, Stat1 signaling is necessary and sufficient for the inhibitory effects of IFN-gamma on cholesterol efflux and ABC1 expression. |
| Interlaboratory cholesterol standardization: a model project Noel, S. A., R. E. Wenk, et al. (1990), Clin Lab Sci 3(4): 237-8. |
| Interleukin 1 stimulates cholesterol esterification and cholesterol deposition in J774 monocytes-macrophages Maziere, C., V. Barbu, et al. (1996), Biochim Biophys Acta 1300(1): 30-4. Abstract: The effects of interleukin 1beta (IL1) in the range of concentration of 10-30 ng/ml on cholesterol metabolism were investigated in the monocyte-macrophage cell line J774. IL1 enhanced cholesterol esterification by 14Coleic acid and acyl-coenzyme A cholesterol acyl transferase activity in a dose-dependent manner. Incubation of IL1-treated cells with acetylated low density lipoproteins labelled with 3Hcholesteryllinoleate resulted in accumulation of radioactive cholesterol in free and esterified form. Concomitantly, IL1 increased the free and esterified cholesterol intracellular content measured by the cholesterol oxidase technique. The effect of IL1 on cholesterol esterification by oleic acid was not observed in the presence of cycloheximide or of the ACAT inhibitor Sandoz 58 035. IL1 also stimulated cholesterol esterification in other cell types such as human fibroblasts and murine endothelial and smooth muscle cells. The effect of IL1 is specific, since IL2 or tumor necrosis factor (TNF) exhibited no significant activity, whereas oncostatin M only slightly enhanced cholesterol esterification. Since cholesterol deposition is involved in the initiation and progression of the atherosclerotic lesions, these findings highlight the role of the inflammatory cytokine IL1 on this process. |
| Interleukin 8 is induced by cholesterol loading of macrophages and expressed by macrophage foam cells in human atheroma Wang, N., I. Tabas, et al. (1996), J Biol Chem 271(15): 8837-42. Abstract: In order to identify novel genes expressed in macrophage-derived foam cells, we used a multigene assay to examine the expression of genes in control versus cholesterol-loaded macrophages. We compared THP-1 macrophages incubated with or without acetylated LDL (acLDL) +/- acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor (compound 58035) for 20 h and assessed changes in mRNA of chemokines, growth factors, interleukins, and adhesion molecules. Among 49 genes examined, an increase in mRNA was observed only for interleukin 8 (IL-8) in THP-1 macrophages. Northern analysis confirmed a 3- to 4-fold increase of IL-8 mRNA and an enzyme-linked immunosorbent assay (ELISA) revealed a corresponding increase in IL-8 in conditioned medium. Oxidized LDL (oxLDL) also induced IL-8 mRNA, but native LDL had no effect. 58035 had a moderate effect on IL-8 induction by acLDL. AcLDL-induced IL-8 expression was concentration- and time-dependent. The time course of IL-8 induction paralleled that of cholesterol loading. MCP-1, a chemokine implicated in recruiting monocytes in atherogenesis, was also induced by acLDL. The induction of MCP-1, however, peaked at 1 h after addition of acLDL and returned to basal level by 20 h while IL-8 induction peaked at 8 h and was still 2-fold higher than basal level at 20 h. IL-8 induction was also observed in fresh human monocyte-derived macrophage cells treated with acLDL. Finally, immunohistochemistry and in situ hybridization studies using specimens of human coronary atheromas showed expression of IL-8 mRNA in a macrophage-rich area. We conclude that IL-8 is induced in macrophage foam cells as a response to cholesterol loading. The chemoattractant and/or mitogenic effects of IL-8 on neutrophils, T cells, smooth muscle, or vascular endothelial cells may contribute to the progression and complications of atherosclerosis. |
| Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages Cornicelli, J. A., D. Butteiger, et al. (2000), J Lipid Res 41(3): 376-83. Abstract: Activated subpopulations of lymphocytes and mast cells have been detected in atherosclerotic lesions. Interleukin-4 (IL-4) is a prominent cytokine released during activation of both cell types and its transcripts have been detected in both human and mouse atherosclerotic lesions. To define whether this local release of IL-4 influences macrophage lipid metabolism, we examined the effects of this cytokine on intracellular cholesterol esterification during incubation with modified low density lipoprotein (LDL). IL-4 greatly augmented cholesterol esterification induced by acetylated LDL (AcLDL) in both mouse peritoneal macrophages and the murine macrophage cell line, J774. This augmentation was maximal at a concentration of 1 ng/ml after incubation for 48 h. This was not a generalized effect on lipoprotein metabolism as IL-4 had no effect on cholesterol esterification in the presence of either LDL or beta-VLDL. Determination of binding isotherms demonstrated that IL-4 increased the number of cell surface binding sites for AcLDL. The IL-4-augmented AcLDL-induced cholesterol esterification was attenuated by the scavenger receptor class A (SR-A) antagonist, fucoidan, and the anti-mouse SR-A monoclonal antibody, 2F8. These data, combined with the known receptor specificity of AcLDL interactions, imply a role of SR-A in the IL-4 induced responses. Two cytokines that have been demonstrated previously to down-regulate SR-A, TNF-alpha and TGF-beta, antagonized the IL-4-induced augmentation of cholesterol esterification. Therefore, local release of IL-4 within atherosclerotic lesions could have a profound effect on macrophage lipid metabolism and the subsequent atherogenic process. |
| Interleukin-6 genotype is associated with high-density lipoprotein cholesterol responses to exercise training Halverstadt, A., D. A. Phares, et al. (2005), Biochim Biophys Acta 1734(2): 143-51. Abstract: BACKGROUND: High-density lipoprotein cholesterol (HDL-C) and its subfractions are modifiable with exercise training and these responses are heritable. The interleukin-6 (IL6)-174G/C polymorphism may be associated with HDL-C levels. We hypothesized that the IL6-174G/C polymorphism would be associated with plasma HDL-C response to exercise training. METHODS AND RESULTS: Sixty-five 50- to 75-year-olds on a standardized diet were studied before and after 24 weeks of aerobic exercise training. Significant differences existed among genotype groups for change with exercise training in HDL-C, HDL3-C, integrated HDL4,5NMR-C, and HDLsize. The CC genotype group increased HDL-C more than the GG (7.0 +/- 1.3 v. 1.0 +/- 1.1 mg/dL, p = 0.001) and GC groups (3.3 +/- 0.9 mg/dL, p = 0.02); for HDL3-C, the CC group increased more than the GG (6.1 +/- 1.0 v. 0.9 +/- 0.9, mg/dL p < 0.001) and GC groups (2.5 +/- 0.7 mg/dL, p = 0.006). Integrated HDL4,5NMR-C increased more in the CC than GG group (6.5 +/- 1.6 mg/dL v. 1.0 +/- 1.3 mg/dL, p = 0.01), as did HDLsize compared to the GG (CC: 0.3 +/- 0.1 v. GG: 0.1 +/- 0.1 nm, p = 0.02) and GC (0.0 +/- 0.0 nm, p = 0.007) groups. CONCLUSIONS: IL6 genotype is associated with HDL-C response to exercise training. |
| Interleukin-8 mediates downregulation of tissue inhibitor of metalloproteinase-1 expression in cholesterol-loaded human macrophages: relevance to stability of atherosclerotic plaque Moreau, M., I. Brocheriou, et al. (1999), Circulation 99(3): 420-6. Abstract: BACKGROUND: The accumulation of macrophage-derived foam cells in atherosclerotic lesions correlates with increased local release of matrix-degrading metalloproteinases (MMPs) and a thin fibrous cap. The activity of these enzymes is controlled by specific tissue inhibitors of metalloproteinases (TIMPs). METHODS AND RESULTS: Because oxidized low-density lipoprotein (OxLDL) modulates gene expression, we investigated the effect of these particles on the levels of MMP-1, MMP-3, MMP-9, TIMP-1, and TIMP-2 in the culture media of human monocyte-derived macrophages. OxLDL but not native LDL or high-density lipoprotein reduced the level of TIMP-1 in a dose-dependent manner with maximal effect (60% of control) at approximately 100 microg protein/mL. In addition, Northern blotting revealed marked reduction in the abundance of TIMP-1 mRNA in OxLDL-treated cells. Evaluation of the effect of oxysterol components of OxLDL on TIMP-1 production revealed that 25-hydroxycholesterol (1 microg/mL) was the most potent inhibitor (approximately 30% of control). Such inhibition was partially mediated by interleukin (IL)-8. Indeed, IL-8 (2.5 ng/mL) induced maximal inhibition of TIMP-1 accumulation (30% of control) in 4 of 6 cell preparations. In addition, the inhibitory effect of OxLDL-treated cells in the presence of an anti-IL-8 neutralizing antibody was partially reversed. CONCLUSIONS: Immunohistochemical analyses of human atherosclerotic plaques revealed the expression of TIMP-1 in some but not all macrophage-rich and IL-8-rich areas. Therefore, IL-8 may play a potential atherogenic role by inhibiting local TIMP-1 expression, thereby leading to an imbalance between MMPs and TIMPs at focal sites in the atherosclerotic plaque. |