摘要:

Previously it has been reported that Greenland Inuit (Eskimos) from the Uummannaq district display low levels of plasma cholesterol and triglycerides and relatively high levels of high density lipoprotein (HDL) when compared with healthy Danish control subjects (Lancet 1971;1:1143-1146). Here we present data obtained in 1989 that show the following. In a group of 133 healthy adult Greenland Inuit from Nanortalik, the levels of plasma cholesterol and low density lipoprotein (LDL) cholesterol (639 and 4.39 mmol/l, respectively) were slightly higher than "normal" values found in western societies, whereas the HDL cholesterol level was markedly higher (1.64 mmol/l). Compared with most Caucasian populations, the Inuit population we studied exhibits a high apolipoprotein (AP0)E*4 allele frequency (0229), whereas the AP0E*2 allele frequency was extremely low (0.015). In contrast to Caucasian populations, in the Inuit population the apoE polymorphism showed only a minor influence on the plasma lipid and (apo)lipoprotein levels, as evaluated by multiple regression analysis, with the exception of apoE levels. This absence of an effect could be explained by the low very low density lipoprotein (VLDL) plus intermediate density lipoprotein (IDL) cholesterol levels. The contributions of eicosapentaenoic acid and linoleic acid to the total amount of fatty acids in plasma cholesterol esters differed markedly from those reported in 1971 for another Greenland Inuit population (3.2% versus 15.8% and 49.5% versus 20.4%, respectively), thereby resembling values now found in the average western population. Even in those Inuit who reported exclusive consumption of the traditional Inuit diet (13% of the population), the fatty acid composition of the plasma cholesterol esters closely resembled the values measured in western populations. More than 89% of the Inuit regularly drink alcohol. Alcohol consumption was associated with lower levels of VLDL+IDL cholesterol, LDL cholesterol, and apoB and an elevated level of apoAl and HDL cholesterol. In addition, alcohol consumption was associated with a decreased contribution of linoleic acid and an increased contribution of eicosapentaenoic acid to the total amount of fatty acids in plasma cholesterol esters. Smoking, a common habit in the present-day Inuit, had only a weak influence on the plasma apoB level. In conclusion, when compared with the findings of Bang, Dyerberg, and coworkers in the early 1970s among the Uummannaq Inuit, we found in the Inuit from Nanortalik higher levels of most plasma lipids and (apo)lipoproteins and a more western fatty acid composition of plasma cholesterol esters.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We have previously demonstrated that rat aortic allografts from the DA (RT1a) to the WF (RT1a) strain develop chronic arteriosclerotic changes in the vascular wall after a short spontaneously reversible acute rejection episode. These changes, which are lacking in syngeneic DA-to-DA control grafts, are virtually identical with those observed in human allografts during chronic rejection. In this study we have investigated whether eicosanoids are involved in the generation of arteriosclerotic changes. Incubation of aortic wall rings in vitro and immunochemical assays demonstrated that the arteriosclerotic allografts synthesize significantly more thromboxane B2(TxB2) but not 6-ketoprostaglandin F1α(6-keto-PGF1α) or leukotriene B4. The increased synthesis of TxB2in the allografts persisted for at least 5 months after transplantation. Separate incubation of the two major components of the vascular wall, after microdissectioa of the intima and (media phis) adventitia, demonstrated that most of the synthesis of TxB2during chronic rejection was due to the outer layer of aorta, presumably the inflammatory cells of the adventitia. In contrast, most of the 6-keto-PGF,» was synthesized by the inner layer of the aorta, presumably the endothelial cells and the smooth muscle cells of the intima. Administration of 1 ing · kg−1· day−1of a specific TxA2receptor inhibitor, GR32191B, to the recipient rat reduced the proliferative response of inflammatory cells in the adventitia by 30%, as detected by in vivo tritiated-thymidine (3H-TdR) labeling and autoradiography, but did not reduce the proUferatlve response of smooth muscle cells in the media and intima. The drug also delayed the intlmal thickening and the generation of aUograft arteriosclerosis by 1 month but was unable to inhibit it indefinitely.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The Paris Prospective Study is a long-term Investigation of the factors predicting coronary heart disease in a large population of middle-aged men. The first follow-up examination involved 7,152 subjects, who were natives of metropolitan France and were free of any cardiovascular history. At that time, the usual cardiovascular risk factors and plasma insulin levels were recorded. An index of body fat distribution, the iliac-to-thigh ratio, was entered into the list of predictive variables, despite the fact that it had been measured 1 year before the first follow-up examination. After 11 years of mean follow-up, 129 of the men had died of coronary heart disease. Univariate analysis showed that the iliac-to-thigh ratio (p<0.0001) and plasma insulin level (both fastingp<0.003] and 2-hour postload [p<0.02]), as well as the four major risk factors of coronary heart disease (age, smoking, blood pressure, and plasma cholesterol level) were significantly higher in subjects who died of coronary heart disease compared with those who had died of another cause or were alive at the end of follow-up. In multivariate stepwise logistic regression, the iliac-to-thigh ratio appeared as an independent predictor of coronary heart disease death, thereby causing the removal of fasting insulin level from the list of significant independent predictors. Nevertheless, in a model that entered 2-hour postload insulin in two classes (high or low), both the insulin level and iliac-to-thigh ratio were found as significant independent predictors. These results suggest that much of the already demonstrated predictive power of plasma insulin levels could be mediated through their association with upper-body fat distribution. However, 2-hour postload insulin concentration appears to improve the prediction and may denote the existence of metabolic abnormalities that are not entirely summarized by the type of fat distribution.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Interferon gamma (IFN-y) is a multifunctional tymphokine secreted by activated T lymphocytes, which are found in atherosclerotic lesions. IFN-y has been reported to suppress the proliferation of vascular smooth muscle cells (SMCs). However, as we report in this paper, IFN-y is mitogenic for vascular SMCs under certain circumstances. Recombinant human IFN-y (1–100 units/ml), in a dose-dependent fashion, stimulated cell multiplication and [3H]thymidine and 5-bromo-2′-deoxyuridine incorporation into DNA by cultured arterial SMCs that had been growth arrested by culturing in 1% plasma-derived serum for 5 days. IFN-y also accentuated the mitogenic activity of platelet-derived growth factor (PDGF)-BB. A time-course study revealed that there was a time lag of 4-6 hours between the G,&#151;>S transition of quiescent SMCs stimulated by IFN-y and that of SMCs stimulated by PDGF-BB. A synergistic effect of IFN-y on the mitogenicity of PDGF became apparent after a similar time lag, suggesting that the IFN-y-related mitogenicity is mediated by a substance(s) secreted by IFN-y-treated SMCs. In fact, conditioned medium of IFN-y-treated SMCs was mitogenic for SMCs. Mitogenic activity in the conditioned medium was also detected by an assay using Swiss 3T3 cells, which originate from mice and, therefore, are not responsive to human IFN-y. The production of the mitogenic factor was blocked by antWFN-y antibody. Mitogenicity of the conditioned medium was not eliminated by addition of neutralizing antibody against PDGF, indicating that any autocrine growth factor(s) secreted by IFN-y-treated SMCs was not PDGF. This was supported by the fact that '"I-PDGF-AA binding to SMCs was not decreased by prior treatment with EFN-y. Contrary to the lack of effects on the PDGF or-receptor, IFN-y treatment increased '"I-PDGF-BB binding to SMCs by 20-50%. Scatchard plot analysis revealed that this increase in '"I-PDGF-BB binding was due to increased binding sites on the cell surface. Northern blot analysis showed that the increase of the PDGF 0-receptor was regulated at the level of mRNA. Based on these observations, we conclude that IFN-y under certain circumstances stimulates proliferation of vascular SMCs by both inducing production of an autocrine growth factor(s) and upregulating PDGF $-receptor expression. The mitogenic activity of IFN-y may play a role in atherogenesls and other inflammatory processes.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The aim of this study was to investigate the possibility that the permeability characteristics of the arterial wall are related to the development of atherosclerosis. The in vivo regional variation of aortic permeability to iodinated human low density lipoprotein (LDL) in normal rabbits was compared with the regional variation in aortic cholesterol accumulation in cholesterol-fed rabbits. Aortas were divided into the aortic arch, thoracic aorta, and abdominal aorta, and each of these three parts was further subdivided into four segments of similar size. The permeability to LDL was 40±7 nl &#149; cm"2&#149; hr"1(mean±SEM, n=ll) in the most proximal segment of the aortic arch and decreased throughout the length of the aorta to 3±1 nl &#149; cm"2&#149; hr"1in the most caudal segment of the abdominal aorta. In such normal rabbits the aortic cholesterol content was similar in all 12 arterial segments at 0.08 ±0.005 μnol/cm1(mean±SEM, n=3xL2). Aortic cholesterol accumulation was determined in other rabbits with an average plasma cholesterol level of 32±1 mmol/l for 96 days; the cholesterol content in the most proximal segment of the aortic arch was 2.7±0.5 μmol/cm2(mean±SEM, n = ll) and decreased with increasing distance from the heart to 0.17±0.03 μsnol/cm1in the most caudal segment of the abdominal aorta. Linear regression analysis showed a close positive association between the permeability to LDL of a given aortic segment and the cholesterol accumulation in that same aortic segment after cholesterol feeding (r2=0.96,p<0.001). These results suggest that the aortic permeability to LDL is an important predictor for the development of atherosclerosis in cholesterol-fed rabbits.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Using 2-16% gradient gel electrophoresis, we examined low density lipoprotein (LDL) particle size in relation to plasma lipoproteins in 1,168 women and 1,172 men from the Framingham Offspring Study. In addition, we studied the effect of dietary intake on LDL size in a subset of the population. Seven LDL size peaks were identified, with the largest, LDL 1, being found in the density range 1.019-1.033 g/ml; LDL 2 and LDL 3 in d= 1.033-1.038 g/ml; LDL 4 and LDL S in d= 1.038-1.050 g/ml; and the smallest, LDL 6 and 7, in d=1.050-1.063 g/ml. Seventy-seven percent of the population had one major and at least one minor LDL peak. Secondary LDL peaks accounted for 23% of the total LDL relative area, based on laser scanning densitometry. LDL size distribution was skewed toward larger LDL particles in women (prevalence of LDL 1, 30% and of LDL 2, 31%), whereas men exhibited a more symmetric distribution (prevalence of LDL 3, 42%). The prevalence of small (<255 A), dense (d>1.038 g/ml) LDL particles 4-7 was 33% in men, 5% in premenopausal women, and 14% in postmenopausal women. In agreement with previous reports, small, dense LDL particles were significantly (p<0.0001) associated with increased triglyceride and apolipoprotein (apo) B levels and decreased HDL cholesterol and apo A-I levels. In addition, we found a significantp»< 0.0001) association between LDL cholesterol and LDL size. The highest LDL cholesterol levels were found among women with LDL 4 (148 mg/dl) and men with LDL 3-5 (138 mg/dl). In addition, the presence of LDL 3 or 4 as secondary peaks was significantly associated with higher LDL cholesterol levels, while smaller secondary LDL peaks were associated with higher triglyceride levels. We also found that compared with subjects with optimal LDL cholesterol levels (<130 mg/dl), individuals with high-risk LDL cholesterol levels (a 160 mg/dl) had 1) a higher prevalence of LDL 3 and 4 (women only) and a lower prevalence of LDL 1 and 2 (women only) and 2) 11% higher LDL cholesterol to apo B ratios, even when matched for LDL particle size. Furthermore, low saturated fat and cholesterol intakes were significantly associated (p<0.01) with smaller LDL particles. Therefore, the identification of small, dense LDL particles per se may not be a good indicator of coronary artery disease risk in population studies. Gender differences and environmental factors that affect triglyceride levels and LDL physical and chemical properties should be taken into consideration. In addition, LDL 3-5 particles in men and 4 in women are associated with the highest LDL cholesterol levels.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The effect of human platelets on the adhesion of polymorphonuclear leukocytes (PMNs) to cultured endothelial cells was investigated. Resting platelets inhibited the adhesion of PMNs stimulated by JV-formyl-methionyl-leucyl-phenylalanine (fMLP), leukotriene B4 (LTB4), and tumor necrosis factor-α (TNF-α). Platelets similarly inhibited PMN adhesion induced by endothelial cell activation with TNF-o. The inhibitory effect depended on platelet number, was not associated with detectable platelet activation, and was also exerted by paraformaldehyde-fixed platelets. Moreover, supernatants of U46619- or thrombin-stimulated platelets were ineffective, thus excluding a role for constituents released as a result of the platelet-release reaction. Strong inhibition of PMN adhesion was exerted by platelet lysates. The inhibitory activity associated with lysates was sedimentable, heat sensitive, and not dialyzable through a membrane with a molecular-weight cutoff of 8,000; it was directed toward PMNs and was not due to cytotoxic effects or a general inhibition of PMN responsiveness to stimulation, since enzymatic release from activated PMNs was unaffected by platelet lysates. Finally, the activity was not prevented by specific adenosine inhibitors and anti-P-selectin monoclonal antibody. These data suggest that resting platelets can exert an inhibitory effect on PMN adhesion to the vessel wall during inflammatory and thrombotic conditions.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Cell seeding may decrease the thrombogenicity of implanted vascular grafts, but its application is hampered by the limited availability of autologous endothelial cells. We studied the interaction of alternate cells, human peritoneal mesothelial cells, with whole blood in a flow chamber. When titrated blood was perfused over mesothelial cells, platelet adhesion was seen on the intercellular matrix but not on the cells themselves. Pet-fusions with blood anticoagulated with low-molecular-weight heparin resulted in fibrin formation at the surface of mesothelial cells but not at the surface of human umbilical venous endothelial cells. At shear rates of 200 sec~' fibrin deposition on the mesothelial cell surface increased during the first 5 minutes to 5.7 ±1.06fi%fibrin per square centimeter, whereafter these values stabilized. The procoagulant activity of cultured mesothelial cells was higher than that of peritoneal membrane studied ex vivo. However, cultured mesothelial cells incubated with polyclonal antibodies against tissue factor showed a significant decrease in procoagulant activity. We conclude that human peritoneal mesothelial cells may be used for cell seeding procedures, provided that their tissue factor expression can be controlled.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Lipoprotein lipase (LPL) that is associated with the luminal surface of capillary endothelial cells hydrolyzes circulating lipoprotein triglyceride molecules. Because LPL is synthesized by cells on the abluminal side of endothelial cells, LPL must contact both the ablumlnal as well as the luminal sides of the endothelium. To determine whether LPL interacts identically with apical (luminal) and basolateral (abluminal) sides of endothelial cells, we investigated binding, transport, and cellular uptake of LPL presented to each side of bovine aortic endothelial cell monolayers grown on semipermeable filters. When LPL was included in the medium on either the apical or basolateral side of the cells, a similar amount of LPL was found in the medium on the opposite side of the cells. Heat-inactivated LPL crossed the monolayers more rapidly in both directions. When cell surface LPL was assessed, more LPL bound to the apical than the basolateral endothelial cell surface. Release of cell surface-associated LPL was assessed with the use of heparin. Less heparin was required to dissociate apical-surface LPL. When LPL (4 μg/ml) was in contact with the apical surface for 1 hour, 32.8±4.9 ng LPL per 24-mm filter were internalized by the cells. If the LPL was in the basolateral medium, only 6± 1.8 ng LPL were found inside the cells. Heat Inactivation decreased LPL binding to cell surfaces and internalization by the cells. LPL interactions with the cells were also studied morphologically by using Texas Red (TR) -labeled LPL and confocal microscopy. More TR-LPL was associated with and internalized by the apical endothelial surface. Incubation of cells with TR-LPL in the basolateral medium led to accumulation of LPL on the apical surface, suggesting that the LPL was transported across the cells. Inclusion of TR-LPL on the apical surface did not lead to appreciable accumulation of LPL on the basolateral cell surface. Therefore, endothelial cells are polarized to accumulate LPL on the apical surface. In addition, more LPL is internalized from this side of the cells. We postulate that the polarity of endothelial cells allows LPL to collect at its physiological site of action, i.e., on the luminal surface.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

A nonocclusive silicone cuff placed around the rabbit carotid artery results in a diffuse intimal thickening. The early stages of this phenomenon were studied by light microscopy, immunohistochemistry, and electron microscopy. Neointimal formation appeared to be triphasic. The first phase started 2 hours after cuff placement, with vascular infiltration by polymorphonuclear leukocytes (PMNs). In the second phase, starting within 12 hours, 1.90±0J6% of the medial smooth muscle cells (SMCs) were replicating, as demonstrated by their immunoreactivity for proliferating cell nuclear antigen (PCNA). The third phase was characterized by the appearance, from day 3 onward, of subendothelial SMCs that were immunoreactive for α-SMC actin and vimentin. A few cells showed immunoreactivity for PCNA. During this phase all the PMNs disappeared, but SMC replication in the media was still present, as indicated by the presence of mitoses and the persisting immunoreactivity for PCNA (0.76±0.22% at day 7). In the third phase the number of subendothelial cells increased (104±15 SMC nuclei per section at day 7, of which 8.89±2.26% were PCNA-positive) and was associated with deposition of collagen type IV and flbronectin. At 14 days a complete, circular neointima was present and contained 2.13 ±0.28% replicating SMCs. The media showed 0.44±0.08% cell-cycling SMCs, which was still four times higher than normal. During the first week there was also a significantly higher PCNA activity in the media of sham-operated carotid arteries (no cuff present) than in nonsurgical ones. However, this did not lead to the formation of a neointima. We conclude that in the cuff system SMC replication in the media precedes the neointimal formation. The system can be used to study SMC replication, migration, and neointimal formation with minimal medial SMC damage.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID