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

Foam cell formation via lipid accumulation through the scavenger receptor in human monocyte/macrophages is believed to be one of the earliest events in atherogenesis. In this study we demonstrate that stimulation of the scavenger receptor activates monocytes to produce interleukin-1 (IL-1). Polyinosinic acid (poly I) and fucoidan, both ligands known to bind to the scavenger receptor, induced IL-1 beta production in human monocytes. Polycytidylic acid, a structurally related compound to poly I, which does not bind to the scavenger receptor, was used as a negative control and had virtually no effect on IL-1 production. THP-1 cells, which normally do not express scavenger receptors, were almost unresponsive to poly I and fucoidan. PMA priming, which has been reported to up-regulate scavenger receptor expression in THP-1 cells, significantly enhanced IL-1 production by fucoidan and poly I. IL-1 produced by scavenger receptor stimulation was shown to be secreted extracellularly, and biologically active. Scavenger receptor-mediated IL-1 production was inhibited by H7, a protein kinase C inhibitor, and enhanced by IBMX, an inhibitor of cyclic AMP degradation, suggesting a synergistic effect of protein kinase C and cyclic AMP-mediated signal transduction pathways in scavenger receptor-mediated IL-1 production. Due to the potentially deleterious effects of IL-1 on the vessel wall, IL-1 produced by ligand binding to the scavenger receptor in human monocytes may play a role in the pathogenesis of atherosclerosis.
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PMID:Induction of interleukin-1 production by ligands binding to the scavenger receptor in human monocytes and the THP-1 cell line. 166 75

Besides the well established role of low density lipoproteins (LDL), the phospholipid PAF-acether (paf) seems to be involved in atherogenesis. The effect of LDL (10 micrograms/ml for 24 h, n = 3) on paf binding characteristics of monocyte/macrophage-like U 937 cells was investigated using the radioligand [3H]paf, unlabeled paf and the paf receptor antagonist WEB 2086. The specific [3H]paf binding significantly increased at 1.4 nM (P less than 0.02) and 2.8 nM (P less than 0.01) added [3H]paf with an increased number of paf binding sites in the Scatchard plot analysis of the data. Specific paf binding was functionally active since paf mediated a cellular [Ca2+]i rise. The protein kinase C (PKC) activator PMA (1 nM, 37 degrees C) expressed specific [3H]paf binding already after a 15-min incubation period, indicating a PKC activation as the decisive step of paf receptor expression. LDL also stimulated the paf degrading cellular acetylhydrolase significantly by increasing both Km (9.4 +/- 1.9 vs. 2.0 +/- 0.5 microM, P less than 0.02) and vmax (0.5 +/- 0.2 vs. 0.2 +/- 0.0 nmol/min per mg cell protein, P less than 0.02). The data demonstrate that LDL increases the number of paf receptors on monocyte/macrophage-like U 937 cells and interferes with the dynamics and/or synthesis of the cellular acetyl hydrolase. These effects could be of importance in the pathogenesis of atherosclerosis.
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PMID:Long time incubation of monocytic U 937 cells with LDL increases specific paf-acether binding and the cellular acetylhydrolase activity. 180 64

The molecular genetic defect of a female patient with apolipoprotein A-I (apoA-I) deficiency and premature atherosclerosis was examined. Her parents were first cousins. Her plasma density fraction from 1.063 to 1.21 g/ml contained no apoA-I on SDS/PAGE and no measurable high density lipoprotein cholesterol. Southern blot hybridization showed no gross abnormality to be present in the patient's apoA-I gene and homozygosity for a haplotype of restriction fragment length polymorphisms in the apoA-I gene region. Sequencing after amplification by PCR revealed a codon 84 nonsense mutation (CAG----TAG, Gln----stop) of exon 4 and a codon 67 missense mutation (GCC----ACC, Ala----Thr) of exon 3 in the patient's apoA-I gene. The data from dot-blot hybridization with allele-specific oligonucleotide probes indicated that she was homozygous for the apoA-I gene with regard to the two mutations. The codon 37 missense mutation was also detected in the apoA-I gene of 6 out of 60 controls, who all had normal levels of apoA-I and high density lipoprotein cholesterol, suggesting that the missense mutation is polymorphic and not associated with apoA-I deficiency. These findings indicate that homozygosity for the apoA-I gene with codon 84 nonsense mutation causes the deficiency of apoA-I and of high density lipoprotein cholesterol in the patient.
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PMID:Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. 190 17

We report a 39-year-old Japanese man with HDL and apoA-I deficiency as well as data from members of his family. Corneal opacity and a stomatocyte were found but not tonsillar hypertrophy, xanthomas, or splenomegaly. His serum HDL cholesterol, apoA-I, apoA-II, and LDL cholesterol levels were t mg/dL, < 3 mg/dL, 6 mg/dL, and 175 mg/dL, respectively. Plasma triglyceride, phospholipid, apoB, apoC-III, and apoE levels were all within normal limits. Lecithin:cholesterol acyltransferase activity was half of normal, while lipoprotein lipase and hepatic triglyceride lipase activities were within normal limits. ApoA-I deficiency was confirmed by combined isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by an immunoblotting method. We surveyed the apoA-I gene of the patient and five of his family members by direct sequencing after amplification by polymerase chain reaction and found a codon 8 nonsense mutation (TGG --> TAG, Trp --> stop) in exon 3 of the apoA-I gene. The results of a pedigree analysis by DNA sequencing and restricted fragment length polymorphism (Sty I) were consistent with an autosomal codominant trait. Coronary angiography was performed to evaluate coronary atherosclerosis, but no significant luminal narrowing was detected. An intracoronary ultrasound study showed mild intimal hyperplasia in segment 6. In summary, this is a case of apoA-I deficiency without evidence of coronary heart disease.
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PMID:A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease. 758 66

Because fibroblast growth factors (FGFs) modulate important functions of endothelial cells (EC) and smooth muscle cells (SMC), we studied FGF expression in human vascular cells and control or atherosclerotic arteries. All cells and arteries contained acidic (a) FGF and basic (b) FGF mRNA. Northern analysis detected aFGF mRNA only in one of five control arteries but in all five atheroma tested, while levels of bFGF mRNA did not differ among control (n = 3) vs. plaque specimens (n = 6). Immunolocalization revealed abundant bFGF protein in control vessels (n = 10), but little in plaques (n = 14). In contrast, atheroma (n = 14), but not control arteries (n = 10), consistently exhibited immunoreactive aFGF, notably in neovascularized and macrophage-rich regions of plaque. Because macrophages colocalized with aFGF, we tested human monocytoid THP-1 cells and demonstrated accumulation of aFGF mRNA during PMA-induced differentiation. We also examined the expression of mRNA encoding FGF receptors (FGFRs). All cells and arteries contained FGFR-1 mRNA. Only SMC and control vessels had FGFR-2 mRNA, while EC and some arteries contained FGFR-4 mRNA. The relative lack of bFGF in plaques vs. normal arteries suggests that this growth factor may not contribute to cell proliferation in advanced atherosclerosis. However, aFGF produced by plaque macrophages may stimulate the growth of microvessels during human atherogenesis.
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PMID:Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and nonatherosclerotic arteries. Association of acidic FGF with plaque microvessels and macrophages. 769 61

Superoxide production by macrophages and leukocytes may have an important role in atherogenesis. Whether lipoproteins modulate the superoxide production of these cells is not clear. Therefore, the effect of lipoproteins on the production of superoxide by rat peritoneal macrophages was tested. VLDL and LDL inhibited digitonin-stimulated superoxide production in a dose-dependent manner. Maximum inhibition was observed at 10 micrograms ml-1 of VLDL protein and 50 micrograms ml-1 of LDL protein respectively. In contrast, HDL (40 micrograms protein ml-1) enhanced digitonin-stimulated superoxide production (by 47 per cent). Macrophage superoxide production induced by arachidonic acid was enhanced by both VLDL (130 per cent) and HDL (84 per cent), whereas LDL had no effect. The lipoproteins had no effect on macrophage superoxide stimulated by other agonists such as phorbol myristate 13-acetate, sodium fluoride or the calcium ionophore, A23187. The effect of lipoproteins was also tested on human polymorphonuclear leukocyte superoxide generation, stimulated by digitonin and PMA. Ten micrograms of VLDL, 50 micrograms of LDL and 50 micrograms of HDL proteins ml-1, inhibited digitonin-induced superoxide production by 50, 100 and 33 per cent respectively. Lipoproteins had no effect on PMA stimulated superoxide generation by human polymorphonuclear leukocytes. The stimulatory and inhibitory effects of lipoproteins on macrophage and neutrophil superoxide generation could be important in the understanding of oxidation-mediated development of atherosclerosis.
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PMID:Effect of lipoproteins on macrophage superoxide generation. 775 48

We examined the influence of transient myocardial ischemia on the number and function of neutrophils in patients with effort angina (EA). We tested fluorometrically the expression of neutrophil membrane molecules (CD11b, CD11c, CD18) and neutrophil oxidative burst using a chemiluminescence (CL) generation system. The estimations were conducted before, 1 min after and 20 min after percutaneous transluminal coronary angioplasty (PTCA) in 15 patients qualified for the treatment because of single-vessel disease. Eight EA patients subjected to coronary arteriography (CA) comprised a control group. We did not observe any marked changes in leucocytosis or lymphocyte number in peripheral blood (PB) or in coronary sinus blood (CSB) after the procedure. The percentage of granulocytes in coronary blood decreased significantly 20 min after reperfusion. No significant changes in white blood cell count were noted in peripheral blood of PTCA patients or in control CA subjects. Oxidative burst of nonstimulated and fMLP, PMA and zymosan stimulated sinus blood neutrophils was significantly depressed 1 min after inflation, and enhanced 20 min after reperfusion. We found a significant increase in the percentage of the CD11c+ neutrophils from 56.7 +/- 7.4% to 64 +/- 6.5% 20 min after inflation and postischemic decrease in the CD11c molecule expression on CSB neutrophils. Significant positive linear correlation (Rval = 0.71) between inflation time and the CD11c molecule expression on CSB immediately after reperfusion was also noted. The results may reflect local activation of neutrophils in ischemic myocardium as a response to ischemia induced increase of activating stimuli.
Atherosclerosis 1994 Apr
PMID:The effect of short-term myocardial ischemia on the expression of adhesion molecules and the oxidative burst of coronary sinus blood neutrophils. 791 25

Alterations of vascular smooth muscle cell (VSMC) proliferation have been implicated in the age-dependent susceptibility to atherosclerosis. Although it is known that protein kinase C (PKC) is involved in the mechanism of VSMC proliferation, there are no data on the possible involvement of PKC in disregulating VSMC proliferation in aged vascular cells. We evaluated the proliferative pattern, the PKC responsiveness and the effect of phorbol ester (PMA) treatment on vascular cell growth and cell cycle distribution in VSMCs from young and aged rats. The proliferative response was significantly higher in aged than in young cells after serum stimulation (7.5 vs. 2.8 x 10(4), 18 vs. 12 x 10(4), 26 vs. 22 x 10(4) cells/well, aged vs. young at days 2, 4, 6; P < 0.005). On the contrary, aged cells showed a significant inhibition of DNA synthesis at 48 h incubation with PMA concentrations of 1, 10, 100 nM (-47%, -53%, -58%, respectively) compared with controls (fetal calf serum 0.5%) and cell count (average decrease: -38% from 48 h to 96 h) after treatment with PMA 10 nM. The opposite was observed in young cells on [3H]thymidine incorporation with PMA 1, 10, 100 nM (+52%, +100%, +121%, respectively and cell count (average increase +55% from 48 h to 96 h). In addition, inhibition of the cell cycle from G1 to the S phase and reduction of PKC translocation in aged VSMC were observed. Alterations of PKC function could be involved in the disregulation of aged VSMC proliferation, which seems to characterize the increased susceptibility to atherosclerosis.
Atherosclerosis 1993 Dec
PMID:Protein kinase C pathway and proliferative responses of aged and young rat vascular smooth muscle cells. 814 37

We have compared the uptake of desialylated low density lipoprotein (LDL) with other modified forms of LDL in mouse peritoneal macrophages and PMA-activated human U937 monocytes. Neuraminidase-treated LDL (NT-LDL) caused significant cholesterol ester accumulation in both cell types, although the efficiency relative to loading with acetylated LDL (AcLDL) was markedly different, suggesting a very different complement of receptors in the cells. We therefore determined the effect of PMA-activation on lipoprotein receptor expression in U937 cells and found that while scavenger receptor concentration was elevated after PMA-activation, there was no significant change in the expression of the LDL receptor. Receptor specificity of NT-LDL uptake was examined by competition experiments using the degradation assay. This showed that 125I-labelled NT-LDL uptake in U937 cells could largely be accounted for by the persistent expression of the LDL receptor in these cells. In contrast, in mouse peritoneal macrophages where LDL receptor expression is very low, 125I-labelled NT-LDL degradation was also effectively competed by asialofetuin. Surprisingly, 125I-labelled NT-LDL degradation was also effectively competed by AcLDL. Measurement of sialic acid content of AcLDL showed that approximately 14% of the LDL sialic acid, equivalent to 2 to 3 residues per particle, was lost during acetylation of LDL with acetic anhydride. Thus competition between 125I-labelled NT-LDL and AcLDL could be due to lectin receptor binding rather than competition for scavenger receptor binding.
Atherosclerosis 1996 Mar
PMID:Desialylated LDL uptake in human and mouse macrophages can be mediated by a lectin receptor. 867 20

In series of patients with stroke, selected by random (n = 68), mean age 62.44 +/- 9.12 years (range 39-82 yrs), there were 23 females (33.8%), mean age 65.43 +/- 10.11 yrs and 45 males (66.2%) mean age 60.8 +/- 8.3 yrs. Lp(a) reference values have been obtained from a group of 283 healthy individuals (age ranging from 15 to 65 years). The cholesterol, triacyglycerol, Apo B reference values come from the database of the Department of Clinical Biochemistry. There were 52 hypoxemic stroke patients in the whole observed group. Triacylglycerol serum level TAG < or = 2.89 mmol/l was observed in 47 cases (90.3%), the serum level TAG > 2.89 mmol/l was present in 5 cases (9.7%). The occurrence of TAG normal serum level was significantly more frequent than its pathologic increase (p < 0.001). Apolipoprotein Apo B < or = 1.67 g/l serum level was present in 41 (78.8%) and Apo B > 1.67 g/l in 11 (21.2%) cases (p < 0.001). Apo B < or = 1.67 g/l serum levels in 23 cases (82.1%) and Apo B > 1.67 g/l in 5 cases (18%) were observed among the stroke diabetes mellitus patients (n = 28)--statistic difference in 1/1000 level. In the total hypoxemic stroke group (n = 52), Lp(a) < or = 0.278 g/l was observed in 44 cases (84.6%), Lp(a) > 0.278 g/l serum level was present in 8 cases (15.4%)/ - p < 0.001. According to EASD consensus the serum level of Lp(a) = 0.278 g/l has been considered as "cut-off limit". Similar distribution of Lp(a) serum levels was observed in the diabetes mellitus stroke group (n = 28), the ischemic heart group (n = 54), the group with aortosclerosis (n = 16) and in the group with arterial hypertension (n = 50). Elevated TAG serum levels were not in correlation with the number of sites where atherosclerotic changes were proved by arteriography, ultrasound investigation e.g. in the extracranial brain supplying arteries. Elevated Lp(a) serum levels did not correlate with the stage of ischemic heart disease and they correlated with the stage of functional CNS defect in arterial hypertension and atherosclerosis. Metabolic disorders of lipoprotein and apolipoprotein, namely genomic transcription of lipoprotein seem to be more significant risk stroke factors, but, if they are present, they contribute to the occurrence of arteriosclerosis of some larger arteries. Elevated Lp(a) serum levels did not correlate with the stage of the heart ischemic disease and aortosclerosis, but they correlate with the stage of functional CNS defect due to arteriosclerosis and arterial hypertension, hence the increase in Lp(a) serum level as an indicator of arteriosclerotic evolution of cerebral arteries is significant. Our results, hence, do confirm a common supposition for Lp(a) serum level as an independent arteriosclerotic risk factor of the brain arteries. (Fig. 7, Tab. 1, Ref. 22.)
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PMID:[Selected parameters of lipoprotein metabolism in cerebrovascular diseases]. 870 23


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