ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Coronary heart disease risk factor levels were studied in 184 first-degree relatives (sisters and brothers) of non-insulin-dependent diabetic subjects (124 relatives with normoglycemia, 34 relatives with impaired glucose tolerance [IGT], and 26 relatives with non-insulin-dependent diabetes mellitus [NIDDM]) and in 215 relatives of nondiabetic subjects (194 relatives with normoglycemia and 21 relatives with IGT). Subjects with IGT exhibited the highest insulin responses to an oral glucose load. Systolic blood pressure was significantly higher; serum high density lipoprotein cholesterol level was significantly lower; and total, low density lipoprotein, and very low density lipoprotein triglyceride levels were higher in the relatives with a family history of diabetes who had IGT or NIDDM than in the normoglycemic relatives without a family history of diabetes. These abnormal changes were not seen in normoglycemic relatives or relatives with IGT who had no family history of NIDDM. Thus, in relatives of diabetics, abnormal glucose tolerance seems to induce changes in cardiovascular heart disease risk factor levels that are similar to those observed in NIDDM. Therefore, a family history of diabetes adds substantially to the risk for atherosclerosis, particularly in subjects with IGT.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Increased expression of tissue factor procoagulant by peripheral blood monocytes has been implicated in a number of thrombotic disorders. The present studies were undertaken to determine whether stable analogues of prostacyclin, a potent endothelium-derived platelet inhibitor and vasodilator, could inhibit tissue factor expression by human monocytic cells. Exposure of monocytic tumor THP-1 cells to 100 ng/ml endotoxin, 2 units/ml interleukin-10β, or 5 ng/ml tumor necrosis factor-α for 4 hours led to increased tissue factor procoagulant activity. Preincubation for 30 minutes with iloprost, ciprostene, and carbacyclin led to a dose-dependent inhibition of tissue factor expression induced by all three challenging agents. Iloprost was the most potent: 50% inhibition occurred at 5 nM, a concentration close to the reported dissociation constant for iloprost binding to the platelet prostacyclin receptor. An orally active analogue, cicaprost, was equally effective against endotoxin-induced tissue factor expression. Carbacyclin and ciprostene were 100 times less potent. Iloprost prevented the endotoxin-induced expression of tissue factor antigen on the surface of THP-1 cells, as determined by flow cytometry. Iloprost (500 pM-50 nM) increased intracellular levels of cyclic AMP. This effect was potentiated by isobutylmethylxanthine, an inhibitor of phosphodiesterase. The inhibitory effects of iloprost on tissue factor expression were also potentiated by isobutylmethylxanthine and mimicked by forskolin and dibutyryl cyclic AMP but not dibutyryl cyclic GMP. These results suggest that prostacyclin may play a role in downregulating tissue factor expression in monocytes, at least in part via elevation of intracellular levels of cyclic AMP.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

In a survey of cardiovascular risk factors in 185 men and 173 women of a Belgian population group, an independent and highly significant positive correlation was found between the serum concentrations of 25-hydroxyvitamin D3and apolipoprotein A-I (p< 0.001 in both sexes). 25-Hydroxyvitamin D3also showed a positive correlation with high density lipoprotein cholesterol levels (p<0.05 in men andp< 0.005 in women). This relation was independent of a possible effect of 25-hydroxy vitamin D3on serum calcium. Taking the biological variation of 25-hydroxyvitamin D3levels (±2 SD=25 ng/ml) into account, these findings could explain variations in the levels of apolipoprotein A-I of 15 mg/100 ml and of high density lipoprotein cholesterol of 4 mg/100 ml.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The effect of fish oil rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on serum lipoprotein concentrations is not clear, and it is not known whether EPA and DHA are similarly related to serum lipid or lipoprotein levels. We conducted a randomized, 10-week, dietary supplementation trial in which the effects of 6 g per day of 85% EPA and DHA were compared with 6 g per day of corn oil in 156 men and women. Multivariate analyses were used to assess independent relations between plasma phospholipid EPA and DHA and serum lipoprotein levels. In the fish oil group triglycerides fell 21% (p<0.001) and high density lipoprotein cholesterol (HDL-C) rose 3.8% (p<0.05). In the corn oil group triglycerides did not change, but HDL-C rose 6.1% (p<0.01). Compared with fish oil, apolipoprotein A-I (apo A-I) rose 5.1% after corn oil intake (p<0.05). Plasma EPA and DHA levels rose after fish oil intake and fell after corn oil intake (allp<0.001). The change (A) in EPA was inversely correlated with Atriglycerides (p=0.035) and positively correlated with AHDL-C and Aapo A-I (bothp< 0.001) in the multivariate analyses. In contrast, ADHA was not correlated with Atriglycerides but was inversely correlated with AHDL-C and Aapo A-I (bothp<0.001). Standardizing for DHA removed the difference in apo A-I levels between groups. This study suggests that EPA and DHA are divergently associated with HDL, possibly through different mechanisms.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

A polymorphicPv1II site was mapped to intron 5 ofLCAT, the gene encoding baboon lecithin: cholesterol acyltransferase (LCAT). In a study of 83 baboons, heterozygous baboons(Pv1/Pv2)had significantly higher LCAT enzyme activity levels than did baboons homozygous for the more common allele(Pv1/Pv1). LCATgenotype explained 6% of the total variation in LCAT enzyme activity. To test for allelic effects on cholesterol metabolism, we compared serum concentrations of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I). We also compared distributions of cholesterol and apo A-I among three HDL size classes (HDL1HDL2and HDL3). All measurements were obtained for each baboon after long-term feeding of a basal diet low in cholesterol and fat and again after 7 weeks on an atherogenic diet. Heterozygous baboons had significantly lower serum levels of total cholesterol than did homozygotes. In addition, we detected significant effects ofLCATgenotype on size distributions of HDL cholesterol and apo A-I on both diets but did not detect any genotype-by-diet interaction. Heterozygotes had increased amounts of cholesterol and apo A-I in HDL3particles and lower amounts of cholesterol and apo A-I in the larger HDL size classes by comparison with homozygotes. Overall, theLCATpolymorphism explained a significant proportion of total variation in cholesterol (4–10%) and apo A-I (13%) distributions on both diets. Thus, the results indicate that theLCATpolymorphism is associated with significant differences in LCAT enzyme activity and with alterations in HDL compositions.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The regulation of apolipoprotein B (apo B) metabolism by eicosapentaenoic acid was investigated in CaCo-2 cells. Cells cultured on semipermeable membranes that separated an upper from a lower well were incubated for 48 hours with albumin alone or 1 mM eicosapentaenoic acid or oleic acid attached to albumin (4:1, mol/mol). Compared with cells incubated with oleic acid, cells incubated with eicosapentaenoic acid synthesized and secreted less [3H]glycerol-Iabeled triglycerides. Although both fatty acids increased cellular triglyceride mass compared with control cells, less triglycerides accumulated in cells incubated with the n-3 fatty acid. The secretion of triglyceride and apo B mass by cells incubated with eicosapentaenoic acid was less than that observed by cells incubated with oleate. The amount of apo B mass within cells, however, was not altered by either of the fatty acids and was similar to amounts found in control cells. Apo B mRNA abundance was decreased fourfold in cells exposed for 48 hours to eicosapentaenoic acid. In contrast, in cells incubated with oleic acid, apo B mRNA levels were not significantly altered. Pulse-chase experiments were performed to investigate the regulation of apo B synthesis and degradation by the fatty acids. In cells incubated with eicosapentaenoic acid, the synthesis and basolateral secretion of newly synthesized apo B-100 and apo B-48 were significantly less compared with control cells or cells incubated with oleic acid. In contrast, the synthesis and secretion of newly synthesized apo B in cells exposed to oleic acid were similar to control cells. Rates of apo A-I synthesis were similar in cells incubated with either of the fatty acids. Compared with control cells and cells incubated with eicosapentaenoic acid, the residence time of labeled apo B in cells incubated with oleic acid was prolonged. The percentage of newly synthesized apo B that was degraded was less in cells incubated with oleic acid. In contrast, residence times and the percentages of apo A-I and apo B-48 degraded were similar in control cells and cells incubated with the fatty acids. Thus, in CaCo-2 cells, compared with the effects of oleic acid, eicosapentaenoic acid impairs triglyceride transport in part by inhibiting apo B synthesis and secretion. The inhibition of apo B synthesis by eicosapentaenoic acid may be related to a decrease in gene transcription or a decrease in mRNA stability, as apo B mRNA levels were significantly decreased in cells incubated with this fatty acid. In contrast, compared with control cells, oleic acid did not increase either the rate of synthesis or the secretion of newly synthesized apo B-100. The monoenoic fatty acid did, however, delay the disappearance of apo B-100 in the cell and decrease the percentage of newly synthesized apo B-100 that was degraded. Because apo B mass secretion was increased by oleic acid, the results suggest that in intestinal cells, there is a preformed pool of apo B that is used for the transport of triglycerides into the lymph.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The incidence of coronary heart disease (CHD) in middle-aged men is more than three times higher in Northern Ireland than in France. The ECTIM study, which is based on WHO MONICA centers in Belfast (Northern Ireland), Strasbourg (eastern France), Toulouse (southwestern France), and Lille (northern France), has been established to investigate this striking difference. Male patients aged 25-64 years with myocardial infarction (MI) and control subjects sampled from the general population were recruited in the four centers. Hypolipidemic drug treatment was much more frequent in France than in Belfast. "Hypercholesterolemia" denned by the presence of hypolipidemic drug treatment or a low density liproprotein cholesterol level >200 mg/dl was more frequent in cases than in controls in both countries but was similar in both control groups. An in-depth study of lipid variables, including measurements of cholesterol fractions, triglycerides, apolipoproteins (apo), and lipoprotein particles (Lp), was performed in nonhypercholesterolemic subjects. In Northern Ireland and France, patients in comparison with controls had lower levels of high density lipoprotein cholesterol, apo A-I, apo A-II, Lp A-I, and Lp A-II: A-I and higher levels of Lp E:B and Lp(a):B. The levels of triglycerides, very low density lipoprotein cholesterol, apo B, and Lp C-III:B were higher in cases than in controls only in Belfast. In control subjects, the mean levels of cholesterol fractions and apolipoproteins were similar in Northern Ireland and France; however, the level of Lp A-I was lower and the levels of Lp E: B and Lp(a): B were higher in Northern Ireland than in France. A high-risk profile, characterized by a low Lp A-I level and by high levels of Lp E: B and Lp(a): B, was thus more frequent in the population of Northern Ireland. Further studies are needed to determine the contribution of environmental and genetic factors to this risk profile and to investigate its predictive value within populations.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

α-N-acetyl-L-lysine methyl ester (NALME) is a lysine analogue that reportedly binds to low-affinity lysine binding sites in plasmin(ogen) and miniplasmin(ogen). In the studies presented here, we show that NALME has antifibrinolytic activity; however, unlike the therapeutic agents e-amino-n-caproic acid (eACA) and tranexamic acid (TEA), the activity of NALME is based on inhibition of the plasmin active site. NALME (0.1-10 mM) significantly inhibited the amidase activity of plasmin, miniplasmin, and streptokinase-plasmin complex without affecting er-thrombin or tissue plasminogen activator. eACA and TEA (0.1-10 mM) did not affect the amidase activity of plasmin or miniplasmin. A kinetic analysis showed that NALME is a competitive inhibitor of D-Val-L-Leu-L-Lys-p-nitroanilide HC1 (S-2251) hydrolysis by plasmin; NALME binding to plasmin completely prevented S-2251 binding. TheK, for the plasmin- NALME interaction was 0.4 mM. eACA and TEA inhibited fibrin monomer digestion by plasmin and miniplasmin without binding to the active site of either enzyme. This result suggests that eACA and TEA function as antifibrinolytics by disrupting the noncovalent association of fibrin monomer with a domain common to both plasmin and miniplasmin (probably kringle 5). NALME inhibited fibrin monomer digestion principally by decreasing amidase activity. NALME was the only lysine analogue that prevented fragment X formation; TEA and eACA primarily inhibited the formation of fragments Y and D. When plasmin was incubated simultaneously with o$-antiplasmin and a2-macroglobulin, eACA increased the fraction of plasmin reacting with o$-macroglobulin; NALME had no effect on the plasmin distribution. eACA, TEA, and NALME increased the euglobulin clot lysis time of normal plasma. NALME did not prolong the prothrombin time or activated partial thromboplastin time. These studies demonstrate that the antifibrinolytic activity of NALME is based on inhibition of the plasmin active site, whereas eACA and TEA are active due to kringle domain interactions.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

To determine if arterial lipoprotein metabolism may be involved in mediating well-known anatomic regional differences in susceptibility to atherosclerosis, arterial low density lipoprotein (LDL) metabolism and extent of atherosclerosis were studied in 17 ovariectomized female cynomolgus monkeys. The animals were fed an atherogenic diet for 18 weeks, during which time one group received 17β-estradiol and cyclic progesterone treatment (n=9) and the controls received no hormone replacement therapy (n=8). As reported previously, hormone replacement markedly reduced the accumulation of LDL in coronary arteries without affecting plasma lipoprotein patterns. We report here that LDL metabolism differed among arterial sites. LDL accumulation, LDL degradation rate, and the concentration of undegraded LDL were greatest in the coronary arteries and carotid bifurcations compared with the aorta, iliac arteries, and cerebral arteries. Although hormone replacement decreased indexes of LDL metabolism, there was no effect on intimal thickness or indexes of endothelial injury, such as leukocyte adhesion and endothelial cell turnover rate. There were, however, regional differences in these morphological parameters. The intima was thickest in the aorta, and leukocyte adhesion and endothelial cell turnover rates were greatest in the carotid bifurcation and thoracic aorta. The decreased accumulation and metabolism of LDL caused by hormone replacement therapy was specific to the arterial system and did not occur in the liver or other peripheral tissues.

ISSN:1049-8834    

出版商:OVID    

年代:1992

数据来源: OVID