摘要:

Binding of iodine-125-labeled thrombin to fibrin clots from two siblings with juvenile stroke was 30% of normal, and abnormally high amounts of the radioligand (not adsorbed by fibrin) were found in the supernatant. In concordance with this finding, supernatants from the patients' fibrin clots caused abnormal enhancement of platelet aggregation, ATP secretion, and binding of125I-fibrinogen to platelets exposed to subthreshold concentrations of ADP or epinephrine. Hirudin suppressed the enhancing effect of the patients' supernatants, and substitution of y-thrombin for cv-thrombin led to normalization of platelet responses. Under some experimental conditions, degradation of the patients' fibrinogen by plasmin was impaired. However, the euglobulin lysis time, the rate of fibrin degradation by plasmin, and the lysis of the patients' plasma clots by human melanoma tissue-type plasminogen activator were normal. Patients' plasmas, as well as purified fibrinogen, showed a prolonged thrombin time (partially corrected by 10 mM CaCl2) and an impaired release of fibrinopeptide A in response to thrombin. However, the release in response to reptilase was normal, and the reptilase, ancrod, and thrombin coagulase times were within control (normal) values. In addition, the patients' fibrinogen showed normal polymerization of preformed fibrin monomers, normal sialic acid content, and normal binding to ADP or epinephrine-stimulated platelets. Our studies support the concept that thrombin and platelets play an important role in the occurrence of stroke in these patients and suggest a direction to be followed to identify the mechanism(s) contributing to thrombosis in subjects with abnormal fibrinopeptide release.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Cholesteryl ester transfer protein (CETP) mediates an important pathway for reverse cholesterol transport. Concentrations of CETP in fasting plasma were measured by radioimmunoassay in two different groups of hyperlipoproteinemic subjects. Plasma CETP concentrations measured by radioimmunoassay correlated closely with cholesterol ester transfer activity in normal plasma (r=0.86). In the first group of 58 patients, plasma CETP concentrations were significantly increased, as compared with those in 79 normal subjects and in hypercholesterolemic (+26%) and combined hyperlipoproteinemic (+25%) subjects but were not altered in moderately hypertriglyceridemic subjects. Marked elevations in plasma CETP levels were documented in patients with dysbetalipoproteinemia (+68%) and severe chylomicronemia (+85%). Similar results were obtained in a second population of 50 hyperlipoproteinemic subjects. Significant correlations were found between plasma CETP levels and total cholesterol (r=0.52), very low density lipoprotein (VLDL) cholesterol (r=0.63), and apolipoprotein E concentration (r=0.40). Correction of the lipoprotein phenotype by dietary means resulted in significant reductions in plasma CETP concentrations in patients with chylomicronemia and dysbetalipoproteinemia. In these subjects, plasma high density lipoprotein cholesterol concentrations increased as CETP decreased. These studies indicate that CETP levels increase in association with enhanced peripheral cholesterol transport via low density lipoprotein, β-VLDL, or chylomicron remnants.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Angiogenesis results in part from the response of endothelial cells to the integrated action of morphogenic factors and extracellular matrix proteins. In this study we identified specific components of the extracellular matrix that were modulated in endothelial cells derived from bovine aorta and rat cerebral microvessels, both of which spontaneously form cords and tubes under standard culture conditions. SPARC (secreted protein, acidic and rich in cysteine) was upregulated 4.2-fold in aortic and 10-fold in microvascular cultures that had organized into cords and/or tubes. This Ca2+-binding glycoprotein was synthesized primarily by endothelial cells in the process of cord formation. Transcription of type I collagen was initiated in aortic endothelial cells undergoing angiogenesis in vitro and showed a 12-fold increase in similar cultures of microvascular cells. Type VIII collagen protein was upregulated to a lesser degree(4.3-fold in aortic and 1.8-fold in microvascular cells). Dense cytoplasmic staining for these two collagen types was seen in cells directly participating in the organization of cords. In contrast, the disparate levels of fibronectin observed in both types of endothelium indicated an indirect or secondary role for this glycoprotein in cord/tube formation in vitro. These results identify SPARC, type I collagen, and type VIII collagen as extracellular matrix components that are actively synthesized by endothelial cells undergoing angiogenesis in vitro. Moreover, expression of these proteins during the formation of tubes and cords appears to follow a biosynthetic program that is common to endothelial cells from both the macrovasculature and microvasculature.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Previous studies have shown that simvastatin, a hydroxymethyl glutaryl coenzyme A reductase inhibitor, reduces plasma cholesterol levels when administered once a day. In the present study, the efficacy and tolerability of a morning and an evening dose were compared. The dosages employed were 2.5 and 5 mg for 12 weeks. This investigation was a double-blind, placebocontrolled study involving 172 hyperlipidemic subjects whose plasma cholesterol levels were higher than 220 mg/dl. During the study period, mean changes in plasma cholesterol level (from baseline) were &#151;11% with the 2.5-mg q.a.m. regimen, &#151;15% with the 2.5-mg q.p.m. regimen, &#151;14% with the 5-mg q.a.m. regimen, and -21% with the 5-mg q.p.m. regimen. Each of these changes was statistically significant when compared with that in the placebo group (p><0.001). In addition, the reduction in cholesterol level was significantly greater with the evening regimen than with the morning regimen for both the 2.5-mg (p<0.05) and the 5-mg (p<0.05) dosages. The changes in triglyceride and high density lipoprotein cholesterol levels in each group were not significantly different from those in the placebo group. There were no differences in the incidence of clinical adverse reactions among the various treatment groups. In conclusion, when simvastatin was administered orally once per day in the evening, it reduced cholesterol levels to a significantly greater degree than when it was given in the morning.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

To study the possible importance of the low density lipoprotein (LDL) receptor in regulating the degree of postprandial lipemia, a cholesterol-rich fat emulsion was infused into the duodenum of subjects who were divided into four groups based on the expected variation in the expression of the LDL receptor: young men (n=ll), elderly men (n=7), male patients on estrogen therapy (n&#151;5), and patients with familial hypercholesterolemia (n=9). In familial hypercholesterolemia, fasting plasma levels of lipoproteins of d< 1.006 g/ml, intermediate density lipoproteins, and LDLs were increased. During the fat infusion, the cholesterol and triglyceride contents in the d< 1.006 g/ml fraction increased to a similar extent in all groups, whereas a concomitant reduction of LDL cholesterol levels was observed. The degree of the decrease in LDL cholesterol was positively correlated with the observed increase in triglycerides in the </< 1.006 g/ml fraction. There were no signs of accumulation of intermediate density lipoproteins during infusion in any of the groups studied. The results indicate that the capacity for clearance of chylomicrons and chylomicron remnants is not affected by variation in LDL receptor expression.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Previous studies have indicated an inverse relation between circulating high density lipoprotein (HDL) concentrations and the rate of chylomicron clearance. Because chronic exercise has been shown to augment chylomicron clearance, we measured HDL cholesterol concentrations and plasma triglyceride and retinyl palmitate responses to high- (140 g) and low- (50 g) fat meals in endurance-trained men. Plasma HDL cholesterol concentrations in these men ranged from 36 to 105 mg/dl. Intraindividual variation in the cholesterol concentration of the HDLs occurred primarily in HDL2. The magnitude of postprandial lipemia induced by both the highand the low-fat meals was uniformly low compared with values reported previously for sedentary men and was not correlated with HDL cholesterol concentrations. Postprandial retinyl palmitate concentrations, which reflect chylomicron remnant metabolism, also showed no correlation with HDL cholesterol concentrations. These data indicate that the degree of postprandial lipemia is not the primary determinant of HDL cholesterol concentrations in endurance-trained men. Accordingly, the wide range of HDL cholesterol concentrations measured in these men must be attributable to other factors.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

We conducted a cross-sectional analysis of the genetic and environmental contributions to the variance of lipoprotein cholesterol and its subfractions in children during early adolescence. Univariate path analysis was used to determine the relative contributions of genes, individual environment, and family environment to these measures in 233 11-year-old Caucasian twin pairs. For high density lipoprotein, high density lipoprotein2, low density lipoprotein, very low density lipoprotein, and triglycerides, a model that incorporated genes and individual environmental variation but not common environment was sufficient to explain the variation. Different magnitudes of genetic effects were seen for total cholesterol in boys and girls. High density lipoprotein3showed different magnitudes by sex for genetic and individual environmental effect. Intermediate density lipoprotein was the only cholesterol subfraction in which shared, or common, environment was found to make a statistically significant contribution to the variation.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Apolipoprotein (apo) A-IV is a protein involved in the metabolism of chylomicrons and high density lipoproteins. This protein displays genetic polymorphism due to two main codominant alleles, A-IV' and A-IV2. We have identified the mutation that leads to this polymorphism. It is caused by a single-base substitution of guanine for thymine in the third base of codon 360. This substitution leads to a glutamine to histidine change. Direct sequencing of amplified DNA from eight subjects in a three-generation pedigree has demonstrated that the guanine to thymine substitution can explain the apo A-IV polymorphism. In 32 unrelated individuals, a correspondence between apo A-IV phenotype determined by isoelectric focusing and genotype determined with Fnu4HI digestion of amplified DNA could be demonstrated. The enzyme lecithin: cholesteryl acyltransferase (LCAT) is activated by apo A-IV. Under our in vitro conditions, the isoprotein apo A-IV 1-1 is a better LCAT activator than is the isoprotein apo A-IV 2-2. A knowledge of the molecular mechanism underlying the apo A-IV polymorphism will help to elucidate the mechanisms involved in LCAT activation.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The expression of lipoprotein lipase mRNA (LPL mRNA) was studied in rat hearts by use of a sulfur-35-labeled antisense mRNA probe. Rats were studied under three conditions: fed, fasted, and injected with cholera toxin (an irreversible agonist of adenylate cyclase) and then fasted. The highest LPL activity was found in the hearts of cholera toxin-injected, fasted rats. After injection of cholera toxin, LPL mRNA levels were 3.5-fold higher than those from fed rats. Using in situ hybridization, we studied the site of expression of LPL mRNA under the same three experimental conditions. In sections of hearts from cholera toxin-injected, fasted rats, concentrations of autoradiographic grains, representing the site of LPL mRNA, were seen over interstitial elements, which comprise capillary and perivascular cells. A more diffuse and sparse reaction was seen over cardiac myocytes and was not always distinguishable from background. A similar but much less definitive localization was seen in sections of hearts from fasted rats. The present results indicate that in the rat heart, the main site of LPL synthesis and processing, especially after stimulation with an irreversible agonist of adenylate cyclase, is localized to interstitial elements rather than to adult cardiac myocytes.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

β-Very low density lipoproteins ($J-VLDLs) are atherogenic, cholesterol-rich chylomicron and VLDL remnants that accumulate in the plasma of type III dysbetalipoproteinemic subjects. To evaluate the effect offish oil supplementation on plasma β-VLDL concentrations, we compared the lipid and lipoprotein responses in nine type III and nine type IV hyperlipidemic subjects. Each individual received 6 g/day o>-3 fatty acids for 12 weeks. Before treatment, the mean total cholesterol, total triglyceride, VLDL triglyceride, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol levels were not different between groups. Conversely, VLDL cholesterol, intermediate density lipoprotein (IDL) cholesterol, and IDL triglycerides were higher in type III than in type IV subjects. Fish oil supplementation was associated with significantly lower levels of cholesterol (-50%), triglycerides (&#151;50%), and apolipoprotein B (&#151;50%) in the d< 1.006 g/ml ultracentrifugation plasma fraction in both groups, compatible with a reduction in VLDL in type III and type IV subjects, and in β-VLDL in type III subjects. This finding was confirmed by analysis of the plasma zonal ultracentrifugation profile and the agarose gel electrophoretic pattern of lipoproteins, which showed a reduction in but not a disappearance of remnant particles, suggesting that not all β-VLDL had been cleared after treatment. The levels of IDL cholesterol and IDL triglycerides(1.006<d< 1.019 g/ml) were not affected in either group. Initially low LDL cholesterol(1.019 <d< 1.063 g/ml) and HDL cholesterol levels rose significantly in both groups. In type III hyperlipidemics, all LDL cholesterol values remained below 120 mg/dl, whereas they were higher than 150 mg/dl after treatment in two individuals with type IV hyperlipidemia. In conclusion, our results demonstrate that fish oil supplementation is equally effective in lowering total triglycerides and triglycerides in the d< 1.006 g/ml plasma fraction in type III and type IV hyperlipidemias. In addition, fish oils reduce chylomicron and VLDL remnant concentrations in type HI dysbetalipoproteinemia.

ISSN:1049-8834    

出版商:OVID    

年代:1991

数据来源: OVID