Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that hormone replacement therapy inhibits the progression of atherosclerosis in postmenopausal women. Focal attachment of monocytes to endothelial cells is observed in early atherosclerotic lesions. The aim of this study was to investigate the effects of 17beta-estradiol (E2) and progesterone on the adhesion of human monocytic THP-1 cells to human female aortic endothelial cells (HAECs) in vitro. Minimally oxidized low-density lipoprotein (LDL) significantly increased THP-1 cell adhesion to HAECs as compared with native LDL at the same concentration. Though E2 inhibited minimally oxidized LDL-induced THP-1 cell adhesion in a dose-dependent manner, progesterone had no significant effects. Preincubation of HAECs with tamoxifen significantly antagonized the inhibitory effect of E2. These findings suggest a beneficial effect of hormone replacement therapy on atherosclerosis.
 ...
PMID:Effects of 17beta-estradiol and progesterone on the adhesion of human monocytic THP-1 cells to human female endothelial cells exposed to minimally oxidized LDL. 925 54

Human serum albumin minimally-modified by methylglyoxal (MGmin-HSA) stimulated the synthesis and secretion of tumour necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells 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 markedly lower synthesis and secretion of TNF-alpha from THP-1 cells than did MGmin-HSA. The median effective concentration EC50 value of MGmin-HSA for the secretion of TNF-alpha was 5.8 +/- 0.3 microM and the maximal secretion was 0.28 +/- 0.01 ng TNF-alpha/ml (n = 12) for incubations containing 5 x 10(5) cells/ml. MGmin-HSA (0.2-2.0 microM) also stimulated chemotaxis of THP-1 cells in vitro but AGE-HSA did not in this concentration range. The EC50 value of MGmin-HSA for the chemotactic response was 0.44 +/- 0.07 microM (n = 15). Similar induction of the synthesis and secretion of TNF-alpha and chemotaxis by monocytes in response to MGmin-HSA in vivo may contribute to atherosclerosis in macro- and micro-angiopathy, particularly in the development of chronic clinical complications of diabetes mellitus.
 ...
PMID:Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. 929 94

Evidence from numerous epidemiological and animal studies has shown a protective effect of estrogens on the development of atherosclerosis. Since not all of the beneficial effects of estrogen can be explained by alterations in plasma lipoprotein profiles, estrogens may have a direct effect on the arterial wall on one or more of the key steps in the pathogenesis of atherosclerosis. In the present study we tested the hypothesis that estrogens decrease macrophage foam cell formation by reducing lipoprotein uptake via the scavenger receptor pathway. Incubation of the human THP-1 macrophage cell line with 17 beta-estradiol reduced the uptake and metabolism of 125 I-labeled human acetylated LDL (acLDL) in a concentration-dependent manner (from 10(-9) to 10(-5) mol/L) by 30% to 40% at the highest concentrations used. This decrease was accompanied by a reduction in cholesterol accumulation and esterification. When chloroquine was used to block lysosomal degradation, 17 beta-estradiol retained its ability to decrease accumulation of acLDL. This finding suggested that the effect of estrogen occurs before degradation of acLDL by lysosomes. 17 beta-Estradiol had no effect on binding of 125I-acLDL at 4 degrees C. When 125I-acLDL was bound at 4 degrees C and warmed to 37 degrees C, less acLDL was internalized and degraded in cells treated with 17 beta-estradiol, due to greater dissociation of the bound acLDL from the surface of estrogen-treated cells during internalization. We conclude that as a result of the estrogen-induced increase in dissociation of acLDL, less lipoprotein cholesterol is delivered to macrophages, resulting in a reduced rate of foam cell formation. This may be one mechanism by which estrogens reduce the development of atherosclerosis.
 ...
PMID:Effect of 17 beta-estradiol on metabolism of acetylated low-density lipoprotein by THP-1 macrophages in culture. 932 65

Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8. This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.
 ...
PMID:Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein. 935 52

We have investigated the effects of oxidized low density lipoproteins (oxidized LDL) on the expression of TM by THP-1 monocytic cells. TM antigen levels and its cofactor activity for thrombin-dependent protein C activation were increased by oxidized LDL and accompanied by an increase in TM mRNA levels. Incubation of THP-1 cells with 300 microg/ml oxidized LDL for 24 h resulted in an 80% increase of cellular TM antigen levels. Native LDL and acetylated LDL did not affect the TM expression by these cells. The resultant aqueous phase after extraction of oxidized LDL by chloroform/methanol increased the TM antigen levels as well as oxidized LDL. Phorbol 12-myristate 13-acetate (PMA) also increased the TM antigen level 2.1 times the control and was accompanied by the adhesion of cells to plastic dishes and increasing macrophage cell surface antigen CD14 levels. In contrast, oxidized LDL did not induce differentiation to the macrophage. The present results indicate that oxidized LDL increases cellular TM antigen without cellular differentiation and that up-regulation of TM by oxidized LDL in monocytes may have some implication in atherosclerosis.
 ...
PMID:Effect of oxidized low density lipoprotein on thrombomodulin expression by THP-1 cells. 936 89

Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) is a potent mitogen for smooth-muscle cells (SMCs) belonging to the EGF family. We have previously determined that HB-EGF is expressed in macrophages and SMCs of human atherosclerotic lesions and that its membrane-anchored precursor, proHB-EGF, also has a juxtacrine mitogenic activity which is markedly enhanced by CD9, a surface marker of lymphohaemopoietic cells. Therefore, when both proHB-EGF and CD9 are expressed on macrophages, they may strongly promote the development of atherosclerosis. In the present study we have investigated the changes in proHB-EGF and CD9 in THP-1 cells during differentiation into macrophages and by the addition of oxidized low-density lipoproteins (OxLDL) and assessed juxtacrine growth activity of THP-1 macrophages for human aortic SMCs. HB-EGF and CD9 at both the mRNA and the protein level were up-regulated after differentiation into macrophages, and further expression of HB-EGF was induced by the addition of OxLDL or lysophosphatidylcholine. Juxtacrine induction by formalin-fixed growth was suppressed to control levels by an inhibitor of HB-EGF and was partially decreased by anti-CD9 antibodies. These results suggest that co-expression of proHB-EGF and CD9 on macrophages plays an important role in the development of atherosclerosis by a juxtacrine mechanism.
 ...
PMID:Role of membrane-anchored heparin-binding epidermal growth factor-like growth factor and CD9 on macrophages. 939 39

Macrophage (M phi) foam cell formation is a characteristic event that occurs in the early stage of atherosclerosis. To examine the roles of activin-A, a member of the transforming growth factor-beta superfamily, and follistatin, the binding protein for activin-A, in M phi function, we investigated their effects on foam cell formation of THP-1 M phi s. When THP-1 M phi s were treated with activin-A (5 nmol/L), foam cell formation and cellular cholesteryl ester accumulation were decreased. This downregulation was paralleled by a reduction in cell association and degradation of acetylated LDL. The inhibitory effect of activin-A on cell association and degradation was dose dependent, and the effect was blocked by concomitant addition of follistatin. Activin-A (5 nmol/L) also decreased the Bmax for acetylated LDL and scavenger receptor mRNA expression. Follistatin showed an effect opposite to that of activin-A and promoted M phi foam cell formation and cellular cholesteryl ester accumulation. It increased binding, cell association, and degradation of acetylated LDL and upregulated scavenger receptor mRNA expression. Because follistatin is the binding protein for activin-A, follistatin's effect is considered to be mediated by blocking the inhibitory effect of intrinsic activin-A. These results indicate that activin-A inhibits and follistatin promotes M phi foam cell formation by regulating scavenger receptor mRNA expression. We conclude that activin-A and follistatin play important roles in the process of atherosclerosis by regulating M phi foam cell formation.
 ...
PMID:Role of activin-A and follistatin in foam cell formation of THP-1 macrophages. 940 6

Monocyte-endothelial cell interactions play an important role in the early stages of atherosclerosis, and it is hypothesized that regulation of metalloproteinase production by these interactions contributes to this pathological process. The effects of monocytic cell-endothelial cell interactions on monocytic metalloproteinase production were investigated using an in vitro system, focusing on the role of endothelial cell secretions and physical contact as effectors in the regulation of monocytic metalloproteinase expression. Human umbilical vein endothelial cells (HUVECs) and the human monocytic cell line THP-1 were used, and changes in the levels of THP-1 metalloproteinase secretion and mRNA were measured. When THP-1 cells were incubated for 18 hours with HUVEC conditioned medium (CM), a four- to eightfold induction of the metalloproteinase MMP-9 was observed at both the mRNA and protein levels; however, levels of another metalloproteinase, MMP-2, were unaffected. The induction of MMP-9 by HUVEC CM was confirmed using freshly isolated human monocytes. A sevenfold increase in MMP-9 levels was observed with apically collected HUVEC CM but not with basally collected CM. THP-1 cells incubated with paraformaldehyde-fixed HUVECs and isolated HUVEC plasma membranes showed an eightfold increase in MMP-9 levels, and measurements of MMP-9 activity found in THP-1 conditioned medium due to either HUVEC contact or HUVEC CM showed a threefold increase. The molecular weight of the endothelial secreted effector molecule(s) was determined to be 30 +/- 6 kd. The data show that endothelial cells through the release of soluble factors and through direct contact with monocytic cells regulate monocytic metalloproteinase production, which has implications for the atherogenic process.
 ...
PMID:Interactions of monocytic cells with human endothelial cells stimulate monocytic metalloproteinase production. 942 37

The incubation of human macrophages with antigen antibody complexes prepared with rabbit anti-LDL and human LDL (LDL-IC) is followed by ingestion of those immune complexes (IC), massive cholesterol ester accumulation, cytokine release and overexpression of the LDL receptor. The massive accumulation of cholesterol esters and overexpression of the native LDL receptor are specifically induced by immune complexes containing native or modified LDL, but not by any other type of IC. We report the results of a series of experiments aimed at defining the receptor preferentially involved in LDL-IC uptake. Flow cytometry studies using CD16, CD32 and CD64 monoclonal antibodies showed a sharp reduction on the expression of CD64 (Fc gamma RI) both by human monocyte-derived macrophages and THP-1 cells after incubation with LDL-IC, suggesting preferential engagement of this type of Fc receptor. Blocking experiments with aggregate-free IgG1 and CD32 monoclonal antibody confirmed that blocking Fc gamma RI prevented both LDL-IC uptake and the upregulation of LDL receptors on THP-1 cells. In contrast, blocking Fc gamma RII did not affect either the uptake of LDL-IC or the expression of LDL receptors on the same cells. The preferential engagement of Fc gamma R-I by LDL-IC suggests a biological difference of LDL-IC relative to other types of IC and opsonized particles. The precise molecular mechanism(s) responsible for the paradoxical upregulation of LDL receptor after the uptake of LDL-IC remain to be elucidated.
Atherosclerosis 1997 Dec
PMID:The uptake of LDL-IC by human macrophages: predominant involvement of the Fc gamma RI receptor. 943 Mar 65

One mechanism by which plasma high-density lipoprotein (HDL) may protect against atherogenesis is by inhibiting the oxidation of low-density lipoprotein (LDL). Recent evidence suggests that paraoxonase, an HDL-associated, calcium-dependent enzyme, may be responsible for the antioxidant action of HDL (Mackness et al., Atherosclerosis 1993;104:129; Mackness et al., FEBS Lett 1991;286:152; Watson et al., J Clin Invest 1995;96:2882; Navab et al., Arterio Thromb Vasc Biol 1996;16:831); in particular, paraoxonase activity inhibits the formation of 'minimally oxidized' LDL by hydrolyzing biologically active oxidized phospholipids (Watson et al., J Clin Invest 1995;96:2882; Navab et al., Arterio Thromb Vasc Biol 1996;16:831). However, antioxidant effects of HDL have also been demonstrated under calcium-free conditions, arguing that this enzyme may not be the only mechanism by which HDL inhibits LDL oxidation (Tribble et al., J Lipid Res 1995;36:2580). Here we have evaluated the role of paraoxonase in prevention of LDL oxidation by using HDL subfractions, isolated from human serum or EDTA-plasma, which display markedly different levels of paraoxonase activity; the abilities of modified forms of HDL to prevent LDL oxidation by cultured human (THP-1) macrophages were also assessed. Paraoxonase activity was substantially lower in HDL prepared from plasma compared to serum HDL; moreover, virtually all of the lipoprotein-associated paraoxonase activity was located in the HDL3 fraction, with HDL2 retaining only 1-5% of the total activity. Despite possessing 5-fold differences in paraoxonase activity, HDL3 isolated from plasma or serum was equally effective in inhibiting LDL oxidation by THP-1 macrophages; furthermore, although plasma HDL3 was more protective than plasma HDL2, the latter did significantly inhibit LDL oxidation. Non-paraoxonase antioxidant constituents of plasma HDL3 were investigated further. ApoHDL3, the totally delipidated form of HDL3, was much less effective than native HDL3; when examined individually, purified apolipoprotein A-II gave greater protection than apo A-I, although this effect was not evident in apo A-II-enriched HDL3. Partial delipidation of HDL3, which removes both neutral lipids and alpha-tocopherol, did not significantly diminish its ability to inhibit LDL oxidation by THP-1 macrophages; phospholipid vesicles prepared from partially delipidated HDL3 also inhibited LDL oxidation effectively. We conclude that, in this model of cellular LDL oxidation, the phospholipid fraction of HDL exerts inhibitory effects which are independent of HDL paraoxonase activity.
Atherosclerosis 1997 Dec
PMID:Evidence for a paraoxonase-independent inhibition of low-density lipoprotein oxidation by high-density lipoprotein. 943 Mar 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>