摘要:

Human atherosclerotic plaques contain numerous smooth muscle cells (SMCs) that express intercellular adhesion molecule-1 (ICAM-1). Expression of ICAM-1 in different cells is known to be regulated by tumor necrosis factor-a (TNF-t*), which has recently been found to be present in the intimal thickening of human arteries. Therefore, we studied the effect of TNF-« on ICAM-1 mRNA content and surface expression in cultured human aortic SMCs by using the methods of Northern blotting and immunofluorescence flow cytometry. Under basal conditions of cultivation, ICAM-1 mRNA was not revealed in SMCs. However, treatment of the cells with recombinant human TNF-« induced substantial levels of ICAM-1 mRNA. The content of ICAM-1 on the surface of SMCs also increased in a doseand time-dependent manner after incubation with TNF-t*. Twenty-four hours of treatment with 10 ng/mL TNF-arled to an approximately 10-fold increase in ICAM-1 surface expression in the SMCs. Under the same conditions, pretreatment of SMCs with TNF-e* resulted in a twofold increase of their adhesiveness for monocytes. In the presence of anti-ICAM-1 monoclonal antibody 10F3, monocyte adhesion to TNF-«-pretreated SMCs was significantly inhibited, suggesting that the observed monocyte-SMC interaction involved the ICAM-1 expressed on SMC surfaces as a result of TNF-<x stimulation. These results led us to propose that TNF-« may act a regulator of functional ICAM-1 expression on the SMC surface and thus can increase the possibility of interactions between mononuclear cells and SMCs in atherosclerotic plaques.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Recent studies suggest that plasminogen activator inhibitor (PAI-1) may be a risk factor for recurrent myocardial infarction. We measured PAI-1 activity and antigen and tissue-type plasminogen activator (t-PA) antigen in 35 (20 nondiabetic and 15 diabetic) subjects with no clinical or electrocardiographic evidence of ischemic heart disease and in 74 (50 nondiabetic and 24 diabetic subjects) who had survived a myocardial infarction in the preceding 6-24 months. Levels of PAI-1 activity (18.7±5.6 versus 12.0±3.8 arbitrary units [AU] per milliliter,p=0.001) and t-PA antigen (7.0±1.9 versus 4.6±2.0 ng/mL,/»=0.001) were significantly higher in diabetic compared with nondiabetic control subjects. Survivors of myocardial infarction had higher levels of PAI-1 activity and antigen and t-PA antigen than control subjects, and the diabetic survivors had higher levels of PAI-1 activity (25.3±6.7 versus 20.1±7.1 AU/mL, p=0.004) and t-PA antigen (10.6±4.3 versus 8.4±3.3 ng/mL, p=0.03) than the nondiabetic survivors. No difference in PAI-1 antigen levels was found between the diabetic subjects and either the nondiabetic control subjects or survivors of myocardial infarction. After venous occlusion in control subjects, there was a significant increase in PAI-1 antigen (mean 26.7%, range 14.1-58.1% in nondiabetics and mean 25.2%, range 6.2-39.7% in diabetics) and t-PA antigen (mean 78.3%, range 13.6-186.2% for nondiabetic and mean 40.7%, range 17.5-76.2% for diabetic subjects), but in the survivors of myocardial infarction, no significant effect of venous occlusion was observed. These results suggest that diabetic subjects have higher PAI-1 activity levels than nondiabetic subjects both after acute myocardial infarction and in the absence of ischemic heart disease. The similar levels of PAI-1 antigen between the diabetic and nondiabetic subjects suggest that increased levels of t-PA-PAI-1 complexes cannot explain the increase in t-PA antigen in diabetic subjects.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Thrombosis represents an important cause of mortality in patients with sickle cell disease, in addition to the complications caused by the primary defect of inherited abnormal hemoglobin. To study the involvement of platelets in these complications, we assessed the biosynthesis of thromboxane A2in samples from 49 patients with sickle cell disease and in 33 control subjects. The urinary excretion of the major arachidonic acid metabolite of platelet origin (11-dehydrothromboxane B2) and of the vascular endothelial cell (2,3-dinor-6-ketoprostaglandin Flo) were very significantly increased (p<0.0002) in the patients. In a small group of patients 0=14), we further investigated the ex vivo response of their platelets to U46619, a stable analogue of thromboxane A2. We observed decreased aggregation and [14C] serotonin release compared with control (p<0.05); similarly, we found impaired p47 protein phosphorylation (p<0.05). In contrast, platelets from these patients responded normally to thrombin (0.1 unit/mL). In vivo desensitization of platelets from these patients to thromboxane may constitute a form of regulation that may prevent the propagation of aggregation by this potent inducer, as has been hypothesized in in vitro studies. Our results may also provide a rationale for using antiplatelet drugs in the prophylaxis of thrombotic complications in sickle cell patients.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Familial combined hyperlipidemia (FCHL) is a genetic disorder characterized by increases in plasma cholesterol and/or triglyceride, elevated apolipoprotein B, and heterogeneous low density lipoprotein (LDL). To examine the relation between plasma triglyceride concentrations and LDL heterogeneity, 13 hypertriglyceridemic FCHL patients with a predominance of small LDL (LDL subclass phenotype B) were treated with gemfibrozil. The distribution of LDL was determined using nondenaturing gradient gel electrophoresis and nonequilibrium density gradient ultracentrifugation. Mean plasma triglyceride levels decreased 55% (p<0.01) after 3 months of treatment. Mean LDL peak particle size remained small (247±4 versus 249±5 A), and the correlation between change in plasma triglyceride concentrations and a change in LDL peak particle size was not significant. Individual changes in LDL flotation rate (Rf) were, however, inversely correlated with changes in triglyceride concentrationR= 0.60,p<0.05). Although mean LDL Rrincreased during treatment (p<0.005) due to an increase in buoyant LDL, dense LDL remained elevated compared with that of a control population. Thus in FCHL patients, small, dense LDL persists despite decreases in plasma triglyceride concentrations.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We determined the effects of two prostacyclin agonists (octimibate and BMY 42393) on the progression of the fatty streak in vivo and on macrophage function in vitro. Hamsters were fed chow plus 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with animals receiving either octimibate (10 or 30 nig/kg per day) or BMY 42393 (30 mg/kg per day). After 10 weeks of treatment, octimibate decreased plasma total cholesterol and triglycerides by 43% and 32%, respectively. Neither agonist affected blood pressure or heart rate. Lesion-prone aortic arches were stained with hematoxylin and oil red O and examined en face. Compared with controls, octimibate and BMY 42393 on average decreased mononuclear cells attached to the luminal surface by 44% and reduced subendothelial macrophage-foam cell number by 56%, foam cell size by 38%, and fatty streak area by 63%. Since octimibate is a putative inhibitor of acyl coenzyme A cholesterol acyltransferase, we studied the effect of both agents on cholesteryl ester metabolism in murine macrophages. At 10 yu.M, octimibate and BMY 42393 decreased cholesteryl ester accumulation in macrophages by 90% and 41%, respectively. Octimibate inhibited cholesteryl ester synthesis by 96% and increased the rate of cholesteryl ester degradation by 52%. Both prostacyclin agonists reduced macrophage scavenger receptor-mediated uptake of acetylated low density lipoprotein by 24-66% and increased cyclic adenosine monophosphate levels. Octimibate and BMY 42393 inhibited the secretion of tumor necrosis factor by 80-88% when macrophages were activated with lipopolysaccharide. At 10 juM, both agents decreased human monocyte chemotaxis to /V-formylmethionyl-leucyl-phenylalanine by 64-79%. The in vitro results with octimibate and BMY 42393 are consistent with the low number of small foam cells quantified in vivo. We suggest that octimibate and BMY 42393 suppress monocyte-macrophage atherogenic activity and cytokine production and thus inhibit the development of early atherosclerosis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Pulse-chase incubations of human plasma with [3H] cholesterol-laden skin fibroblasts or low density lipoproteins (LDL) and nondenaturing two-dimensional electrophoresis were used to study the transfer and esterification of cell-derived unesterified cholesterol (UC) in human plasma lipoproteins. Specific radioactivities ([3H]UC per microgram of UC) were calculated, and net cholesterol mass transfer was quantified using a fluoroenzymatic assay to validate productive transfers of UC between high density lipoprotein (HDL) and LDL. Cellular UC was initially taken up by pre-/3,-HDL and subsequently transferred in the sequence pre-ft-HDL&#151;»pre-#j-HDL->or-HDL&#151;»LDL. During the first 5 minutes of this process, only 5% of cellular cholesterol was esterified in pre-ft-HDL and or-HDL; the remainder reached LDL as UC. Cellular UC accumulating in LDL was then redistributed to various HDL particles via two pathways: 1) the partially LDL receptor-mediated uptake and resecretion of UC by cells and 2) the direct transfer of UC to HDL, mostly to <x-HDL and a small amount to pre-/3-HDL. UC was not transferred from LDL to HDL after inhibition of lecithin: cholesterol acyltransferase (LCAT). The esterification of cellular [3H] cholesterol in plasma was competitively inhibited by the addition of excess unlabeled LDL but not of excess HDL. However, both excess LDL and excess HDL prevented the esterification of cell-derived cholesterol in apolipoprotein B-free plasma. This demonstrated that LDL is the major source of UC to the LCAT reaction and that the transfer of UC from LDL to HDL is LCAT dependent. In conclusion, the effective esterification of cell-derived cholesterol in plasma involves a rapid transfer of UC via HDL particles to LDL, from which it is distributed to pre-/3-HDL and a-HDL. Furthermore, we hypothesize that the transfer per se of cellular UC to LDL forms a cholesterol concentration gradient between cell membranes and HDL and thus a second, reverse cholesterol transport mechanism in addition to the esterification of cholesterol by LCAT.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID