摘要:

Hepatic triglyceride lipase (HL) is thought to play a role in the formation of low density lipoproteins (LDLs) from small very low density lipoproteins (VLDLs) and intermediate density lipoproteins (IDLs). To analyze the possible physiological role of HL in determining LDL buoyancy, size, and chemical composition, HL activity and LDL were studied in 21 patients with coronary artery disease (CAD) and 23 normolipidemic subjects. In both groups, LDL buoyancy and size were inversely associated with HL activity levels. The effect of HL on LDL size was comparable in CAD patients and in normolipidemic subjects. HL appeared to influence LDL lipid composition primarily by affecting the surface lipid components. The free cholesterol content of LDL particles was highly correlated with HL activity in both CAD and normolipidemic individuals. The free cholesterol to phospholipid ratio in LDL particles correlated with HL in both CAD and normolipidemic subjects. When the individuals were separated according to their LDL subclass patterns, pattern B subjects had significantly higher HL than pattern A subjects in both CAD and normolipidemic groups. The analysis of the cholesterol distribution profiles across the lipoprotein density gradient confirmed that LDL buoyancy is affected by HL. These data support the hypothesis that HL modulates the physical and compositional properties of LDL and contributes to the expression of the LDL subclass phenotype. suggesting a physiological role for HL in LDL metabolism.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The effects on plasma lipoproteins and apolipoproteins of replacing corn oil with corn-oil margarine in stick form as two thirds of the fat in the National Cholesterol Education Program (NCEP) Step 2 diet were assessed in 14 middle-aged and elderly women and men (age range, 44-78 years) with moderate hypercholesterolemia (low density lipoprotein cholesterol [LDL-C] range, 133-219 mg/dl [3.45-5.67 mmol/1] at screening). During each 32-day study phase, subjects received all their food and drink from a metabolic kitchen. Subjects were first studied while being fed a diet approximating the composition of the current US diet (baseline), which contained 35% of calories as fat (13% saturated fatty acids [SFAs], 12% monounsaturated fatty acids [MUFAs; 0.8% 18:ln-9trans], and 8% polyunsaturated fatty acids [PUFAs]) and 128 mg cholesterol/1,000 kcal. This baseline phase was followed by a corn oil-enriched diet containing 30% fat (6% SFA, 11% MUFA [0.4% 18:ln-9trans], and 10% PUFA) and 83 mg cholesterol/ 1,000 kcal, and then a corn-oil margarine-enriched diet containing 30% fat (8% SFA, 12% MUFA [4.2% 18 1n-9trans], and 8% PUFA) and 77 mg cholesterol/1,000 kcal. All diets were isocaloric Mean fasting LDL-C and apolipoprotein (apo) B levels were 153 mg/dl (3.96 mmol/1) and 101 mg/dl on the baseline diet, 17% and 20% lower (bothp<0.001) on the corn oil-enriched diet, and 10% and 10% lower (bothp<0.01) on the margarine-enriched diet Mean fasting high density lipoprotein cholesterol (HDL-C) and apoA-I levels were 48 mg/dl (1.24 mmol/1) and 134 mg/dl on the baseline diet, 9% and 0.4% lower on the corn oil-enriched diet (p<0.01 for HDL-C), and 10% and 3% lower on the margarine-enriched diet (p<0.01 for HDL-C). No significant effects of diet on trigryceride, apoA-I, or lipoprotein(a) concentrations were noted. Replacing corn oil with a typical corn-oil margarine in stick form, as is currently available, resulted in a 10-fold increase in dietarytransfatty acid intake as well as 21% and 14% increases in SFA and MUFA intake, respectively, and a 12% decrease in PUFA intake. These changes resulted in higher plasma concentrations of total cholesterol (p=0.039), LDL-C (p=0.058), and LDL apoB (p=0.068) and a less favorable total cholesterol to HDL-C ratio (p=0.037). Both experimental diets resulted in significant reductions in plasma cholesterol relative to the baseline diet; however, the differences resulting from the substitution of the corn-oil margarine for corn oil were associated with a less favorable lipid profile with regard to coronary heart disease risk. We therefore recommend that hydrogenation be minimized during the processing of foods for use in cholesterol-lowering diets.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Based on previous cross-sectional findings, we hypothesized that weight loss could improve several hemostatic factors associated with cardiovascular disease. In a randomized controlled trial, moderately overweight men and women were assigned to one of four weight loss treatment groups or to a control group. Measurements of plasminogen activator inhibitor-1 (PAI-1) antigen, tissue-type plasminogen activator (t-PA) antigen, D-dimer antigen, factor VII activity, flbrinogen, and protein C antigen were made at baseline and after 6 months in 90 men and 88 women. Net treatment weight loss was 9.4 kg in men and 7.4 kg in women. There was no net change (p>0.05) in D-dimer, fibrinogen, or protein C with weight loss. Significant (p<0.05) decreases were observed in the combined treatment groups compared with the control group for mean PAI-1 (31% decline), t-PA antigen (24% decline), and factor VII (11% decline). Decreases in these hemostatic variables were correlated with the amount of weight lost and the degree that plasma triglycerides declined; these correlations were stronger in men than women. These findings suggest that weight loss can improve abnormalities in hemostatic factors associated with obesity.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Seven moderately hypercholesterolemic subjects were studied before and after 10 weeks of simvastatin therapy (20 mg/day). Therapy reduced low density lipoprotein (LDL) cholesterol by 39% (p<0.001), whereas high density lipoprotein and very low density lipoprotein (VLDL) cholesterol were unchanged. Apolipoprotein (apo) B-containing lipoproteins were divided into VLDL, (S, 60-400), VLDL2(Sr20-60), intermediate density lipoprotein (IDLJ (Sf12-20), and LDL (Sr0-12), and metabolic changes were sought in dual-tracer VLDL] and VLDL2turnover studies. VLDL, apoB pool size was unaltered by therapy, as were its rates of synthesis, catabolism, and delipidation to VLDL2. Similarly, the VLDL2apoB pool size was unchanged, but its metabolic fate was altered. The IDL pool size fell significantly (27%,p< 0.01) due entirely to an increased fractional catabolism of the lipoprotein. In our subjects, the circulating mass of LDL apoB decreased (49%,p< 0.01) primarily due to a reduction in its synthesis. Before therapy, 30% of the apoB entering the delipidation cascade in these hyperlipidemic subjects was converted to LDL. On therapy the input remained the same, but direct catabolism from VLDL2and IDL was increased (p<0.05), and as a result only 16% eventually appeared in LDL. These kinetic changes were associated with a fall in particle cholesteryl ester content throughout the delipidation cascade. We also observed a link between LDL kinetics and its subfraction distribution. Simvastatin influences the metabolism of LDL, IDL, and VLDL2but not VLDL,.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

To test the possibility that variations in macrophage lipoprotein lipase (LPL) secretion may constitute one of the hereditary components of atherosclerosis, we evaluated LPL gene expression and secretion in macrophages harvested from inbred mouse strains differing in their susceptibility to the diet-induced development of atherosclerosis. Inflammatory peritoneal macrophages harvested from atherosclerosissusceptible C57BL/6J mice showed twofold to threefold higher basal LPL mass, activity, and mRNA levels than those isolated from atherosclerosis-resistant C3H/HeN mice. We determined LPL secretion and gene expression in the susceptible C57BL/6J (B), resistant A/J (A), and AxB/BxA recombinant inbred strains of mice typed as atherosclerosis resistant (A-like) or atherosclerosis susceptible (B-like). Macrophage LPL secretion and mRNA expression were twofold higher in the susceptible C57BL/6J (B) mice than in the resistant A/J (A) mice. Significantly higher LPL secretion, activity, and gene expression were found in recombinant inbred mouse strains that typed B-like than in those typed A-like. These results indicate that susceptibility to atherosclerosis is associated in inbred mouse strains with high LPL secretion and mRNA levels, whereas lower LPL secretion and mRNA expression are observed in atherosclerosis-resistant mice. These observations suggest a contributive role for LPL in the development of atherosclerosis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Accumulation of monocyte-derived foam cells in focal areas of the arterial intima is a key step in early atherogenesis. We investigated the expression of vascular cell adhesion molecule-1 (VCAM-1), a mononuclear leukocyte adhesion molecule, in the arterial endothelium during the early phases of diet-induced atherogenesis in rabbits in vivo and the regulation of VCAM-1 expression by cytokines in rabbit aortic organoid cultures in vitro. Rabbits were fed either an atherogenic diet (containing 0.3% cholesterol, 9% coconut oil, and 1% corn oil) or an isocaloric control diet (10% corn oil) for 4 days or 1, 3, 6, or 13 weeks. The endothelium in the ascending aorta focally expressed VCAM-1 after only 1 week on the atherogenic diet but before the first appearance of intimal macrophages, as judged by immunohistochemical staining of serial sections. The rabbits that consumed the atherogenic diet for 3 weeks or longer developed lesions in the intima composed of macrophages bearing class II major histocompatibility antigen (MHC-II). Endothelial cells continued to focally express VCAM-1 at sites of MHC-H-positive intimal macrophages for up to 13 weeks. The ascending aortas of control rabbits lacked VCAM-1 or MHC-II-positive endothelium or macrophages at all times studied. These observations demonstrate the focal activation of arterial endothelium as early as 7 days after initiation of an atherogenic diet (at serum cholesterol levels of 308 ±57 mg/dl). In organoid cultures of rabbit thoracic aortas, Gram-negative bacterial lipopolysaccharide or the cytokines interleukin (IL)-lcx, tumor necrosis factor-*, and IL-4, as well as interferon gamma, induced VCAM-1 expression in the endothelium. Our results suggest that the activation of cytokine-inducible endothelial functions, such as expression of VCAM-1, may participate in the initiation of diet-induced atherosclerosis in rabbits.

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

摘要:

To understand the molecular events governing smooth muscle cell (SMC) proliferation in vivo, immediate-early gene (IEG) expression was assessed and related to growth factor ligand and receptor mRNA and SMC DNA synthesis after aortic injury. Balloon catheter injury evoked increases in SMCc-mycand thrombospondin(tsp)within 2 hours. The induction of these IEGs was followed by elevated transcripts to platelet-derived growth factor-A (PDGF-A), transforming growth factor-/31 (TGF-01) and a basic fibroblast growth factor (bFGF) receptor. Whereas PDGF type-/? receptor mRNA was demonstrated in SMCs from control and balloon-injured aortas, no detectable signal was observed for the PDGF type-a receptor. To explore the potential linkage between LEG products and growth factor mRNA expression, cycloheximide was employed to block early protein synthesis after balloon injury. Induction of PDGF-A and TGF-01 was attenuated by cycloheximide, but bFGF induction was unaffected. Moreover, cycloheximide superinduced IEGs and revealed PDGF-B transcripts, which were otherwise undetected. Seven days after aortic injury, a spontaneous increase inc-mycandtspmRNA was noted. This IEG reactivation was followed 12 hours later by a twofold increase in SMC DNA synthesis. These findings corroborate an autocrine mode of SMC proliferation in vivo and suggest that IEG products may control such growth by stimulating growth factor genes.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The effect of soluble factors from the monocyte/macrophage (M0) on cell proliferation and the functional effects of cell-cell contact on the arachidonic acid (AA) cascade were studied with vascular smooth muscle cells (SMCs). Peripheral blood M0s were isolated by adherence or in a Percoll gradient, and alveolar M0s were obtained by lavage. Conditioned medium (CM) was prepared by preincubating M0s with medium alone or by separating SMC and M0 cocultures by a membrane insert Cell proliferation (image analysis) and 6-ketoprostaglandin F1<r(6-keto-PGFla, radioimmunoassay) were measured in SMCs. Labeled prostanoids and other eicosanoid metabolites were isolated by high-performance liquid chromatography from SMCs prelabeled with14C-AA. M0s did not synthesize 6-keto-PGFIo. The CM enhanced proliferation but did not stimulate 6-keto-PGFi«, synthesis in SMCs. However, cell-cell contact in cocultures of SMCs with the same concentration of M0s used to generate CM resulted in increased 6-keto-PGFlasynthesis by SMCs. Since the stimulatory effect of cell contact was not blocked by butylated hydroxytoluene, it could not be attributed to an oxidative burst from M0s. Functional studies showed that the stimulatory effect of cell contact was enhanced by exogenous free AA and by endogenous AA release through A23187. Release of total radioactivity from prelabeled SMCs was enhanced by cell contact, and this effect was blocked by indomethacin (IM). Cell contact did not increase the release of free AA from prelabeled SMCs, even in the presence of IM. Finally, cell contact only stimulated the formation of prostanoids (IM-sensitive eicosanoid metabolites) from prelabeled SMCs. LJpoxygenase and other products of AA were not formed through cell-cell contact. These data showed that M0s express a soluble factor that enhances SMC proliferation without affecting prostanoid synthesis. Subsequent cell contact between SMCs and M0s stimulates prostanoid synthesis, which may possibly serve as a local and focal homeostatic mechanism for the regulation of uncontrolled SMC proliferation in atherogenesis.(Arteriosclerosis and Thrombosis1993;13:220-230) Conditioned medium (CM) was prepared by preincubating M0s with medium alone or by separating SMC and M0 cocultures by a membrane insert Cell proliferation (image analysis) and 6-ketoprostaglandin F1<r(6-keto-PGFla, radioimmunoassay) were measured in SMCs. Labeled prostanoids and other eicosanoid metabolites were isolated by high-performance liquid chromatography from SMCs prelabeled with14C-AA. M0s did not synthesize 6-keto-PGFIo. The CM enhanced proliferation but did not stimulate 6-keto-PGFi«, synthesis in SMCs. However, cell-cell contact in cocultures of SMCs with the same concentration of M0s used to generate CM resulted in increased 6-keto-PGFlasynthesis by SMCs. Since the stimulatory effect of cell contact was not blocked by butylated hydroxytoluene, it could not be attributed to an oxidative burst from M0s. Functional studies showed that the stimulatory effect of cell contact was enhanced by exogenous free AA and by endogenous AA release through A23187. Release of total radioactivity from prelabeled SMCs was enhanced by cell contact, and this effect was blocked by indomethacin (IM). Cell contact did not increase the release of free AA from prelabeled SMCs, even in the presence of IM. Finally, cell contact only stimulated the formation of prostanoids (IM-sensitive eicosanoid metabolites) from prelabeled SMCs. LJpoxygenase and other products of AA were not formed through cell-cell contact. These data showed that M0s express a soluble factor that enhances SMC proliferation without affecting prostanoid synthesis. Subsequent cell contact between SMCs and M0s stimulates prostanoid synthesis, which may possibly serve as a local and focal homeostatic mechanism for the regulation of uncontrolled SMC proliferation in atherogenesis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Probucol was given to rats made diabetic by streptozotodn. Compared with diabetic rats not receiving probucol or with nondiabetic rats, probucol lowered the plasma concentrations of trigrycerkies, phospholipids, cholesterol, and apolipoproteln B. The concentrations of serum chylomicrons and very low density lipoprotein (VLDL) were also reduced. In control and diabetic rats, probucol enhanced the clearance of endogenoushy radiolabeled VLDL from the plasma. Clearances from the plasma of rat lymph chylomicrons or chylomicronlike lipkJ emulsions were slow in diabetic rats. Probucol normalized chyiomicron clearance in diabetic rats primarily by restoring hepatic uptake of remnants, which was decreased in diabetes. In diabetic rats, uptake of chyiomicron remnants was increased in a number of extrahepatic tissues, including the heart and kidney. Probucol significantly decreased uptake in some extrahepatic tissues. Increased plasma clearance of VLDL and chylomicrons was associated with an increase in the apolipoprotein CH/Clll and apolipoprotein E/C ratios. Orally administered probucol was specifically incorporated into lymph chylomicrons, and clearance of probucol from the plasma exactly paralleled the clearance of chyiomicron remnants, as traced with radiolabeled cholesteiyl esters. Chylomicron-like emulsions incorporating probucol were exclusively cleared from the plasma by the liver in normal rats. We conclude that in streptozotodn diabetic rats, probucol is an effective hypolipidemic agent because it promotes the clearance of the trigiyceride-rich lipoproteins.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID