摘要:

During development of atherosclerotic lesions, vascular smooth muscle cells (SMCs) undergo changes both phenotypically and in their cytoskeleton composition. An expression of cytokeratins 8 and 18 in SMCs in plaques of the human superficial femoral artery and of cytokeratin 8 in lesions of the aorta was recently described. Since cytokeratins are epithelial markers generally not found in normal adult vascular SMCs, we performed a detailed immunofluorescence microscopy study using a large panel of antibodies against the various cytokeratin polypeptides and other elements of the cytoskeleton. We included lesions of carotid, common and superficial femoral, iliac, and popliteal arteries; the abdominal aorta; and saphenous vein bypass grafts, as well as primary, restenotic, and transplantation-associated lesions of coronary arteries (n=33). Cytokeratins 8 and 18 were present in myointimal cells of all pathological specimens. Colocalization with smooth muscle ix-actin identified most cytokeratin-positive cells as SMCs. Only very few cells cosynthesized cytokeratin and desmin, whereas the majority of cytokeratin-positive cells were vimentin-positive. This pattern of cytoskeletal protein synthesis is similar to that found in some fetal and/or neonatal SMCs. These findings suggest that the synthesis of cytokeratins in a subset of SMCs of atherosclerotic lesions is a common phenomenon in coronary artery and peripheral vascular disease as well as graft disease and transplantation-associated arteriosclerosis and that the state of these SMCs is of a "dedifferentiated" fetal type.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

A family history of coronary heart disease (CHD) is a known risk factor for CHD. To investigate the possible role of lipoprotein particles in the relationship between family history of CHD and risk of CHD, we performed a case-control study in a sample of adolescents. The case group consisted of 97 adolescents whose parents had suffered a verified myocardial infarction before the age of 55 years. The control group was composed of 194 subjects without any family history of CHD. One case patient was matched to two control subjects for gender, age, and body mass index. In both groups, plasma lipid variables were measured, including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol, apolipoprotein (apo)AI, apoB, apoAI-containing lipoprotein particles without apoAII (LpAI) and with apoAII, and apoB-containing lipoprotein particles with apoE and with apoCIII. Adolescents with a family history of early myocardial infarction had lower plasma levels of HDL-Cp»<.0001), apoAI (p<.01), and LpAI (p<.0001) than control subjects (adjusted for gender, age, body mass index, smoking habits, and oral contraceptive use). No other differences were statistically significant between case and control subjects. The analysis was repeated separately for male and female subjects. In young men, the best predictor of family history of early myocardial infarction was the LpAI plasma level, whereas in young women it was the HDL-C plasma level. Decreased levels of HDL-C and LpAI lipoprotein particles explain part of the relationship between parental history of early myocardial infarction and CHD risk.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Pharmacological doses of estrogens have been reported to increase hepatic catabolism of low-density lipoprotein (LDL) by the LDL receptor (LDL-R) pathway and to increase the concentration of mRNA for the LDL receptor. The induction of LDL-Rs by large doses of estrogen may not be relevant to the role of estrogens under physiological conditions. Furthermore, the mechanisms by which oral contraceptives, a combination of synthetic estrogen and progestin, may modulate LDL metabolism remain largely unexplored. Adult female cynomolgus monkeys were given combination ethinyl estradiol/norgestrel preparations (n=16) for 16 weeks and were compared with a control group that did not receive exogenous sex hormones (n=7). All animals consumed a diet containing 0.25 mg cholesterol/kcal with 40% of calories from saturated fats. After 16 weeks of treatment there was no significant difference in LDL cholesterol (LDL-C) and hepatic LDL-R mRNA concentration between oral contraceptive-treated animals (LDL-C, 242±113 mg/dL; LDL-R mRNA, 0.60+0.31 pg//ig RNA) and control animals (LDL-C, 277±100 mg/dL; LDL-R mRNA, 0.51±0.21 pg/fig RNA). In contrast, the hepatic cholesteryl ester concentration was significantly lower in the oral contraceptive-treated animals (7.28±3.59 mg/g liver) compared with the control animals (16.07±11.86 mg/g liver, P=.01) with no significant difference in hepatic free cholesterol concentration between the groups. Thus, oral contraceptives decrease hepatic cholesterol concentration independent of LDL-R expression. These data support the hypothesis that the increase in LDL-R mRNA abundance and activity observed with pharmacological doses of estrogen may be secondary to depletion of hepatic cholesterol.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We investigated the effects of high plasma lipid levels on platelet adhesion and platelet thrombus formation in nonanticoagulated human blood on collagen fibrils at an arterial wall shear rate of 2600 seconds'1. Nonanticoagulated blood was drawn directly at a flow rate of 10 mL/min for 3 minutes from an antecubital vein of patients with type Ha (n=5) and type lib (n=4) hyperlipoproteinemia over purified human type III collagen fibrils that were positioned on a plastic coverslip in a parallel-plate perfusion chamber. Results were compared with those obtained in healthy individuals with normal lipid plasma levels (n=9). Blood-collagen interactions were quantified by morphometry as platelet-collagen adhesion, thrombus volume, and fibrin deposition. Platelet-collagen adhesion in the two groups of patients was significantly higher than in healthy individuals (70.7 [61.2 to 82.0] and 70.3 [66.4 to 81.0] in types Ila and lib patients, respectively, versus 51.2 [44.5 to 68.6] in control subjects;p<.05. All values are percent median [range]). In contrast, the thrombus volume was similar in the three groups (11.3 [8.0 to 13.0], 9.6 [6.4 to 15.3], and 10.2 [6.8 to 16.1]/tn$/fim1[range], respectively). Differences in fibrin deposition were not observed. Thus, it appears that platelet-collagen adhesion is augmented in patients with type Ila and lib hyperlipoproteinemia, indicating that the process of thrombogenesis is hastened in these patients.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We used nondenaturing polyacrylamide gradient gel electrophoresis to examine the associations of age, adiposity, alcohol intake, and exogenous estrogen with high-density lipoprotein (HDL) subclasses in 427 members of 51 principally Mormon kindreds. The absorbency of protein stain was used as an index of mass concentrations at intervals of 0.01 nm within five HDL subclasses: HDLj,. (7.2 to 7.8 nm), HDL, b (7.8 8.2 nm), HDL, (8.2 to 8.8 nm), HDL 2a (8.8 to 9.7 nm), and HDL 2b (9.7 12 nm). Age and alcohol intake were obtained from questionnaires, and body mass index was computed from clinic measurements as weight (kg)/height (m) 2. The results suggest that HDL, concentrations were higher after menopause than before. Adult men (>18 years old) had significantly higher HDL$ and HDL, b and significantly lower HDL 2b HDL?* levels than younger boys. Compared with the women, adult men had higher levels of HDI$. and HDL, b and lower levels of HDL 2b, HDL 2a and larger-diameter HDL Ja particles. There were no significant differences between the HDL profiles of women and younger boys, suggesting that the divergence in HDL occurs during puberty. Eighty-eight percent of the increase in HDL associated with estrogen replacement in postmenopausal women occurred within HDL, and HDL 2a. Reported alcohol intake in adult men correlated with two HDL regions: one within the HDL 2b region and a second within the HDL, region, whereas in women the positive correlation between alcohol and HDL levels was within the HDL 2b region only. In both men and premenopausal adult women, increasing levels of body mass index were associated with higher levels of HDL$ and lower levels of HDL 2b. Statistical adjustment for HDL cholesterol levels eliminated the significant relations of alcohol with HDL subclasses in both men and women. The adjustment did not eliminate the significant relations of age and body mass index to HDL$ and HDL;,. Thus, gradient gel electrophoresis of HDL subclasses appears to identify important physiological relations that are independent of HDL cholesterol levels.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

1-Oleoyl lysophosphatidic acid (LPA) enhanced binding ofI25I-labeled fibronectin by cultured MG-63 osteosarcoma cells and human fibroblasts in monolayer cultures up to threefold over control levels. For osteosarcoma cells, LPA was minimally active at 0.1 ng/mL (0.2 nmol/L) and reached maximal activity at 10 ng/mL (20 nmol/L). Increased binding was evident within 10 minutes of treatment of cycloheximidetreated cells with LPA and was due to an increase in the number of fibronectin binding sites. LPA also increased the binding of a fragment containing the 70-kDa amino-terminal region of fibronectin that is primarily responsible for the reversible binding of fibronectin to matrix assembly sites on cell surfaces. Removal of LPA resulted in prompt return of fibronectin binding to baseline levels. These results indicate that LPA is an important enhancer of fibronectin-rich matrix deposition by cultured cells, and it may be the active component in serum and lipoprotein fractions that is responsible for enhancing fibronectin deposition.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The effect of cAMP on the in vitro expression of rabbit aortic fibronectin was examined using a previously characterized organ culture system. Elevation of intracellular cAMP in incubated aortic rings by use of forskolin or dibutyryl cAMP (dbcAMP) inhibited the normally observed increase in fibronectin mRNA to levels below that found in unincubated tissue. The effect of dbcAMP on fibronectin mRNA was dose dependent and reversible. dbcAMP did not affect overall protein biosynthesis or the changes in collagen or elastin mRNAs that normally occurred during in vitro incubation, suggesting a selective regulatory effect on fibronectin. The inhibitory effect of dbcAMP on steady-state fibronectin mRNA levels was independent of the dibutyrate moiety, was not a result of cytotoxicity, did not require de novo protein synthesis, and did not appear to occur through a protein kinase A pathway. The data suggested that suppression of fibronectin mRNA levels potentially occurred via an indirect mechanism that may have involved a dbcAMP-induced reduction in intracellular calcium ([Ca2+],) levels. The resultant decrease in [Ca2+]j may have affected fibronectin expression via a reduction in protein kinase C activity but did not depend on a calmodulin or calmodulin kinase I or II mechanism.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We describe a mutation of the low-density lipoprotein (LDL) receptor gene, designated familial hypercholesterolemia (FH)-Espoo, which deletes exon 15 of the LDL receptor gene. The mutant receptor is predicted to lack 57 amino acids, including 18 serine and threonine residues, which are the sites of the clustered 0-linked sugars of the receptor. Studies on 10 carriers of this gene revealed that FH-Espoo is associated with an exceptionally mild form of FH. Thus, in conditions in which cell proliferation was rendered dependent on the function of LDL receptors, lymphocytes from the patients with the FH-Espoo allele had a growth rate intermediate between those from healthy subjects and patients with the FH-Helsinki gene, a mutation known to abolish LDL receptor function. The in vivo fractional catabolic rate of LDL apolipoprotein B was lower than normal in the two FH-Espoo heterozygotes studied. Although higher than those in healthy controls, the serum LDL cholesterol concentrations in patients with the FH-Espoo gene were significantly lower than those in patients with the FH-Helsinki mutation. The thickness of the Achilles tendons was within the normal limits in subjects with the FH-Espoo gene. Our study suggests that moderate varieties of hypercholesterolemia, ie, those not considered to represent FH, may occasionally be due to subtle LDL receptor gene mutations.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

A systematic immunohistochemical study of different stages of atherosclerosis in human aortas was performed using several antibodies. Because oxidation of lipoproteins could be a key event in atherogenesis, an antibody against apolipoprotein B (apoB) from low-density lipoprotein (LDL) modified with the lipid peroxidation-specific aldehyde, 4-hydroxynonenal (4-HNE) (anti-4-HNE-apoB), was raised in rabbits. This antibody recognizing 4-HNE protein adducts was used in concert with an antibody to apo(a) from lipoprotein(a), considered also potentially atherogenic, as well as with an antibody and a monoclonal antibody (mAb) to apoB. Autopsy material from 12 corpses was investigated. The immunohistochemical investigation by the alkaline-phosphatase technique included control specimens regarding postmortem artifacts by autolysis and oxidation. The results from six specimens from five corpses are presented. A positive staining with the antibody to apoB but not with anti-4-HNE-apoB was seen in the normal intima. The thickened intima of early, transitional, and advanced atherosclerotic lesions and atheromata showed a predominantly extracellular staining with all antibodies and the applied mAb. To test the specificity of the staining, antibodies preadsorbed by the appropriate antigens and nonimmune sera were used, giving negative results. These findings indicated a colocalization of epitopes derived from lipid peroxidation of polyunsaturated fatty acids and epitopes specific for apoB and apo(a) during atherogenesis in humans.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

At the Morphometric Reference Center of the World Health Organization-International Society and Federation of Cardiology PBDAY (Pathobiological Determinants of Atherosclerosis in Youth) project, we studied left hemiaortas of 5- through 34-year-old male and female healthy subjects who died of traumatic injury. The subjects were either of European, American, Asian, or African origin. Three hundred fifty-five thoracic and 343 abdominal left hemiaortas, stained and photographed at the Malmo, Sweden, World Health Organization Reference Center, were studied. Lipid and raised lesion extent was evaluated by using computerized techniques. Probability-of-occurrence maps of lipid and raised lesion distribution were obtained by image processing. Our data have shown that the distributions of atherosclerotic lesions in the aortic intimal surface, which were similar in the different ethnic groups, also prevailed in branching regions, where low-blood flow shear stress and turbulence occur. The areas involved by raised lesions and by lipid lesions only partially overlapped. Lipid lesion extent, which was different among the ethnic groups, continuously increased with age in males but not in females, in whom the increase ceased at an age range from 15 through 24 years. This suggests that ethnic and dietary factors influence the extent but not the distribution of atherosclerotic lesions in the human aorta. Probability-of-occurrence maps also provided evidence that not every fatty streak will develop into a raised lesion, or will not develop quickly.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID