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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibition of experimental atherosclerosis by antioxidants and the presence of oxidized LDL (oxLDL) in atherosclerotic lesions indicate that oxLDL may play what is perhaps a primary role in atherogenesis. LDL promotes the growth of arterial smooth muscle cells (SMCs), and oxLDL has cytotoxic effects. Since excessive intimal growth alternating with necrosis is typical of atherosclerotic lesions, we wondered whether these extreme changes in the lesions could be related to the extreme effects of LDL and oxLDL on cells. We therefore examined the effects of increasing LDL oxidation on its capacity to induce cell growth or cell death and whether the latter could be due to apoptosis. Cells of the types present in the atherosclerotic artery used, ie, SMCs (human arterial), macrophages (human macrophage-like cell line THP-1), and human fibroblasts. Growth was evaluated by measuring the synthesis of DNA and culture size (MTT method) and apoptosis by using the in situ labeling of internucleosomally degraded DNA and, in the case of SMCs, the appearance of chromatin condensation. The oxidation of LDL was by UV or Fe ions. Shortly oxidized LDL had a markedly increased growth-promoting effect on all cell types. With prolonged exposure to UV, but not to Fe, LDL became increasingly cytotoxic, and this toxicity was paralleled by the appearance of apoptosis in all cell types. After prolonged UV treatment, low-molecular-weight material from the partially degraded LDL was responsible for the induction of apoptosis. The dual effect of oxLDL, ie, its strong growth-promoting effect or the induction of cell death by apoptosis, depending on the degree of change by oxidation, is compatible with the notion that oxLDL plays a role not only in atherogenesis but also more extensively in the development of the structure typical of the atherosclerotic lesion, with focal excessive growth alternating with necrosis.
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PMID:Contrary effects of lightly and strongly oxidized LDL with potent promotion of growth versus apoptosis on arterial smooth muscle cells, macrophages, and fibroblasts. 863 Jun 68

Regulation of expression of the scavenger receptor is thought to play a critical role in the accumulation of lipid by macrophages in atherosclerosis. Tumor necrosis factor-alpha (TNF-alpha) has been shown to suppress macrophage scavenger receptor function (van Lenten, B.J., and Fogelman, A.M. (1992) J. Immunol. 148, 112-6). However, the mechanism by which it does so is unknown. We evaluated the mechanism by which TNF-alpha inhibited macrophage scavenger receptor surface expression and binding of acetylated low density lipoprotein (aLDL). Binding of aLDL to phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages was suppressed by TNF-alpha in a dose-dependent manner. Inhibition of aLDL binding was paralleled by a reduction of macrophage scavenger receptor protein as detected by the Western blot. TNF-alpha partially decreased macrophage scavenger receptor mRNA steady state levels in PMA-differentiated THP-1 macrophages, a result that was confirmed by reverse transcription-polymerase chain reaction. PMA increased the luciferase activity driven by the macrophage scavenger receptor promoter in the transfected cells, whereas TNF-alpha partially reduced luciferase activity. However, macrophage scavenger receptor mRNA half-life was dramatically reduced in cells treated with TNF-alpha relative to untreated cells. Reduction in macrophage scavenger receptor message in response to TNF-alpha was dependent on new protein synthesis because it was blocked by cycloheximide. These results indicate that TNF-alpha regulates macrophage scavenger receptor expression in PMA-differentiated THP-1 macrophages by transcriptional and post-transcriptional mechanisms but principally by destabilization of macrophage scavenger receptor mRNA.
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PMID:Inhibition of macrophage scavenger receptor activity by tumor necrosis factor-alpha is transcriptionally and post-transcriptionally regulated. 863 19

The etiology of NIDDM is still controversial, with both insulin resistance and decreased insulin secretion postulated as potential important factors. African-Americans and Hispanics have a two- to threefold excess risk of developing NIDDM compared with non-Hispanic whites. Yet little is known concerning the prevalence of insulin resistance and secretion defects in minorities, especially in African-Americans in population-based studies. Fasting and 2-h post-glucose load glucose and insulin levels, insulin-mediated glucose disposal (insulin sensitivity index) (S(I)), glucose effectiveness (S(G)), and first-phase insulin response (acute insulin response [AIR]) were determined in nondiabetic African-Americans (n= 288), Hispanics (n= 363), and non-Hispanic whites (n= 435) as part of the Insulin Resistance Atherosclerosis Study. Subjects received a standard 2-h oral glucose tolerance test on the first day and an insulin-modified frequently sampled intravenous glucose tolerance test on the second day. African-Americans and Hispanics were more obese than non-Hispanic whites. Both African-Americans and Hispanics had higher fasting and 2-h insulin concentrations and AIR but lower S(I) than non-Hispanic whites. No ethnic difference was observed in S(G). After further adjustments for obesity, body fat distribution, and behavioral factors, African-Americans continued to have higher fasting and 2-h insulin levels and AIR, but lower S(I) than non-Hispanic whites. In contrast, after adjustment for these covariates, no significant ethnic differences in S(I) or fasting insulin levels were observed between Hispanics and non-Hispanic whites. Hispanics continued to have higher 2-h insulin levels and AIRs than those in non-Hispanic whites. In this report, the association between S(I) and upper body adiposity (waist-to-hip, ratio) was similar in each ethnic group. Both nondiabetic African-Americans and Hispanics have increased insulin resistance and higher AIR than nondiabetic non-Hispanic whites, suggesting that greater insulin resistance may be in large part responsible for the higher prevalence of NIDDM in these minority groups. However, in Hispanics. the greater insulin resistance may be due to greater adiposity and other behavioral factors.
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PMID:Increased insulin resistance and insulin secretion in nondiabetic African-Americans and Hispanics compared with non-Hispanic whites. The Insulin Resistance Atherosclerosis Study. 863 47

To clarify the etiology of accelerated atherosclerosis in patients with diabetes mellitus, we measured expression of intercellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), and E-selection on the cell surface by enzyme-linked immunosorbent assay and ICAM-1 mRNA content in human umbilical vein endothelial cells exposed to 5.5 mM glucose (NG), 33 mM glucose (HG), or 27.5 mM mannitol plus 5.5 mM glucose (HM).1) Cell-surface ICAM-1 expression in HG and HM cells was maximally increased by 37% and 32% (P < 0.01), respectively. This effect was dependent on glucose concentration in the medium and was found as early as 24 h and maintained until 6 days after exposing cells of HG. However, neither VCAM-1 nor E-selection expression were affected by HG conditions. 2) Both HG and HM induced increased mRNA content between 6 and 12 h after the stimulation. 3) Adhesion of THP-1 cells to endothelial cells exposed to HG and HM was increased, when compared to NG conditions. These results indicate that osmotic effects can induce increased mRNA and cell-surface expression of ICAM-1 via an as yet unknown mechanism.
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PMID:Expression of intercellular adhesion molecules 1 (ICAM-1) via an osmotic effect in human umbilical vein endothelial cells exposed to high glucose medium. 863 95

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

Lipoxins are bioactive eicosanoids that are generated during multicellular events such as inflammation, thrombosis, and atherosclerosis. They have selective actions on peripheral blood cells, in that previous results indicate that lipoxin A4 (LXA4) and lipoxin B4 (LXB4) inhibit neutrophil migration while they are both potent stimuli of peripheral blood monocyte (PBM) chemotaxis and adherence. Here, we report the impact of lipoxins on levels of free cytosolic calcium ([Ca2+]i) in PBM and THP-1 cells (acute monocytic leukemia cells) as well as on the functional responses of these cells. LXA4, but not LXB4, induced a concentration-dependent increase in [Ca2+]i in monocytes that was half-maximal at approximately 200 nM. Prior exposure of the cells to EGTA reduced the LXA4-induced increase in [Ca2+]i by approximately 50 to 60%, indicating the contribution of both intracellular mobilization and external influx in LXA4 Ca2+ regulation. A leukotriene B4 receptor antagonist, ONO 4057, did not significantly alter LXA4-induced [Ca2+]i, while it inhibited the action of leukotriene B4. LXA4 also induced a rise in [Ca2+]i in the monocytic leukemia cell line (time to reach maximum = 15.1 +/- 0.87 s), and both LXA4 and LXB4 stimulated a concentration-dependent THP-1 cell adherence to laminin with concentrations as low as 10(-10)M. In contrast to the findings with LXA4, exposure of THP-1 or PBM to LXB4 was not accompanied by mobilization of intracellular Ca2+. Although both LXA4 and LXB4 stimulate adherence of PBM, they did not evoke superoxide anion generation by these cells, nor did they affect the rate of acidification of extracellular medium by monocytes, as monitored using a microphysiometer. Together, these results indicate that an increase in [Ca2+]i is a component of the signal transduction events following monocyte interaction with LXA4, but not LXB4, and that both LXA4 and LXB4 are potent and selective agonists for THP-1 cells and PBM. Moreover, they suggest that LX display a unique profile of actions with mononuclear cells compared with other known agonists of monocytes, and that LX can direct monocyte-mediated events.
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PMID:Activation of human monocytes and the acute monocytic leukemia cell line (THP-1) by lipoxins involves unique signaling pathways for lipoxin A4 versus lipoxin B4: evidence for differential Ca2+ mobilization. 875 40

The oxidative modification of low-density lipoprotein by macrophages may be an important mechanism in the pathogenesis of atherosclerosis. The human monocytic leukaemic cell line THP-1, when stimulated with phorbol ester, shares many properties with human monocyte-derived macrophages. Oxidation of LDL by these cells was characterised by depletion of alpha-tocopherol, increases in thiobarbituric acid reactive substances and increases in electrophoretic mobility. The LDL particles were also converted to a form which increased accumulation of cholesteryl esters within macrophages. The oxidative mechanism appeared to be dependent upon the presence of thiols in the cellular medium. Oxidation of LDL by THP-1 macrophages, and production of thiols by these cells, were dependent upon the presence of L-cystine in the medium. Furthermore, cellular oxidation of LDL could be partially mimicked by the addition of cysteine to Hams F10 medium. Macrophage-independent oxidation of LDL, mediated by the addition of copper ions, was inhibited by cystine and cysteine in phosphate buffered saline, but not in Hams F10 medium. The glutathione content of THP-1 macrophages was also dependent upon the presence of cysteine or cystine in the medium, but inhibition of glutathione synthesis by buthionine sulfoximine did not prevent the production of thiols or the oxidation of LDL by THP-1 macrophages.
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PMID:Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism. 784 39

Human serum albumin minimally-modified by methylglyoxal (MGmin-HSA) stimulated the synthesis and secretion of macrophage-colony stimulating factor (M-CSF) by mature human monocytes in vitro. Human serum albumin minimally-modified by glucose-derived advanced glycation endproducts (AGEmin-HSA) and human serum albumin highly-modified by glucose-derived advanced glycation endproducts (AGE-HSA) stimulated much lower secretion of M-CSF from human monocytes than did MGmin-HSA. MGmin-HSA and AGE-HSA but not AGEmin-HSA also stimulated the growth of human monocytic THP-1 cells in vitro which was inhibited by polyclonal antibodies to human M-CSF. For MGmin-HSA, the median growth stimulatory concentration EC50 value was 0.24 +/- 0.07 microM and the maximal increase in cell growth was 36% of control cell growth (n = 24). Similar induction of secretion of M-CSF from monocytes in vivo may contribute to atherosclerosis in macro- and micro-angiopathy, particularly in the development of diabetic complications.
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PMID:Synthesis and secretion of macrophage colony stimulating factor by mature human monocytes and human monocytic THP-1 cells induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. 894 11

Serum amyloid A (SAA) has been linked to atherosclerosis because of its ability to remodel high-density lipoprotein by the depletion of apolipoprotein A1, its ability to bind cholesterol, and its presence in the atherosclerotic plaques of coronary and carotid arteries. In the present study, we investigated the induction mechanism of SAA gene in THP-1 monocyte/macrophage cells which play a critical role in the development of atherosclerotic fatty streak and plaque formation. We and others have shown that SAA gene is induced in monocyte/macrophage cells by lipopolysaccharide (LPS). By promoter function analysis, we show that the SAA promoter sequence between -280 and -226 can confer LPS responsiveness. Gel electrophoretic mobility shift assay detected an induced DNA-binding activity in these cells in response to LPS. Characterization of the DNA-binding protein by UV cross-linking, Southwestern blot, and antibody ablation/supershift assays revealed that it is similar to a recently reported nuclear factor designated SAF. These results demonstrated that LPS-mediated SAA gene induction in monocyte/macrophage cells is primarily due to the induction of SAF activity.
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PMID:Involvement of an SAF-like transcription factor in the activation of serum amyloid A gene in monocyte/macrophage cells by lipopolysaccharide. 910 77

Previous studies have demonstrated that atherosclerotic lesions contain apoE synthesized primarily by macrophages. As oxidized LDL has been implicated in the development of atherosclerosis, its effect on macrophage apoE synthesis and secretion was examined. Human monocytic leukemia cells, THP-1, and human monocyte-derived macrophages were exposed to various forms of oxidatively modified LDL for determination of their effect on apoE mRNA and protein levels. Extensively copper oxidized (Cu-oxidized) LDL resulted in a time- and concentration-dependent increase in apoE mRNA and protein as compared to other forms of oxidized LDL, i.e., LDL modified by soybean lipoxygenase (SLO), azoamidinopropane HCl (AAPH), and hypochlorite (HOCl). Consistent with these results, experiments using THP-1 cells transfected with the apoE promoter linked to a luciferase reporter gene indicated that Cu-oxidized LDL was the most potent stimulator of apoE transgene expression. Enhanced apoE expression due to Cu-oxidized LDL was shown to be due to cholesterol accumulation as well as additional factors. HPLC analysis of the various forms of modified LDL revealed that 7-ketocholesterol was the major oxysterol present in Cu-oxidized LDL. AAPH-oxidized LDL contained significantly less 7-ketocholesterol than Cu-oxidized LDL and virtually no 7-ketocholesterol was detected in SLO- or HOCl-oxidized LDL. Northern blot analysis indicated an increase in apoE mRNA in response to increasing concentrations of 7-ketocholesterol. These results elucidate a potential role of oxidized LDL, and specifically 7-ketocholesterol, in the stimulation of macrophage apoE secretion in atherosclerotic lesions.
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PMID:Mechanisms of enhanced macrophage apoE secretion by oxidized LDL. 918 15


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