摘要:

Previous studies have shown that distal mouse chromosome 1 contains the apolipoprotein All (apoAII) gene, encoding the second most abundant apolipoprotein in high density lipoproteins (HDLs), as well as a gene termedAth-1that controls aortic fatty streak development and HDL cholesterol levels in response to a high-fat, high-cholesterol diet. We report genetic studies confirming that the genes are distinct. Using molecular markers for mouse chromosome 1, we have further mapped the two genes, and our results indicate that they are separated by a minimum of 2 cM. We also report evidence that in mice on a low-fat chow diet, the apoAII gene locus influences HDL cholesterol levels. Thus, statistical analysis of two sets of recombinant inbred strains revealed concordant segregation patterns of HDL cholesterol levels and the apoAII gene locus. The effect of apoAII expression on HDL cholesterol levels was further tested by using a congenic strain that exhibits increased apoAII synthesis in comparison to the background strain. The results support the concept that increased synthesis of apoAII results in increased HDL cholesterol levels. Unexpectedly, increased expression of apoAII appeared to promote rather than retard aortic fatty streak development.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The plasma concentration, particle size, and chemical composition of high density lipoproteins (HDLs) are associated with the metabolism of triglyceride-rich lipoproteins (TGRLs). During alimentary lipemia there is active exchange of lipids and apolipoproteins between HDL and apolipoprotein B-containing lipoproteins. Whereas HDL has been assigned a protective role against the development of atherosclerosis, alimentary lipemia has been proposed to represent a potentially atherogenic state. We examined plasma HDL concentration, particle size, and composition and their relations to postprandial TGRLs in 32 postinfarction patients and 10 healthy control subjects after intake of a standardized oral fat load of a mixed-meal type. All patients had undergone coronary angiographies in connection with the myocardial infarction and around 5 years thereafter. The plasma HDL cholesterol concentration decreased significantly in response to the oral fat load, particularly in hypertriglyceridemic patients, with a concomitant increase of HDL triglycerides. A limited and reversible yet consistent increase of HDL particle size (1–2%) was seen 6 hours after intake of the oral fat load on nondenaturing gradient gel electrophoresis (GGE) in both patients and control subjects. Virtually no changes in the plasma concentration of HDL GGE subclasses, lipoproteins containing apolipoprotein A-I but no apolipoprotein A-II (LpA-I), or lipoproteins containing both apolipoproteins A-I and A-II (LpA-I:A-II) were induced in the postprandial state despite massive increases of large very low density lipoprotein (VLDL) and large chylomicron remnant levels (determined as apolipoproteins B-100 and B-48 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Strong inverse correlations with fasting plasma HDL cholesterol and the larger HDL GGE subspecies were found for large postprandial VLDL and large chylomicron remnants, whereas the corresponding relations for small VLDL and small chylomicron remnants were weaker. The relations of both large and small VLDL and chylomicron remnants to HDL cholesterol were confined to subjects in the lower fasting plasma HDL cholesterol range (<1.2 mmol/l). None of the HDL parameters measured, either in the fasting or in the postprandial state (HDL cholesterol, HDL triglycerides, HDL GGE subclasses, LpA-I, and Lp A-I: A-II), were related to the development of coronary atherosclerosis, whereas the postprandial plasma levels of small chylomicron remnants, which showed weak negative correlations with HDL, related positively to the progression of coronary atherosclerosis. The data suggest that the link between postprandial plasma levels of small chylomicron remnants and the progression Sof coronary artery disease is not accounted for by close metabolic interrelations with the HDL system, a concomitant low HDL cholesterol concentration, or inefficient reverse cholesterol transport, but is instead explained by a direct atherogenic action of the small chylomicron remnants per se.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Rat serosal mast cells, when stimulated to exocytose their cytoplasmic granules, effectively blocked the copper-mediated oxidation of low density lipoproteins (LDLs) in vitro. This effect depended on the proteolytic activity of the formed extracellular granule remnants, since specific inhibition of chymase, the neutral protease that they contain, blocked the protective effect of the mast cells. The mechanism of this chymase-mediated inhibition of LDL oxidation was found to be binding of the copper ions present in the incubation medium by peptides released from LDL on proteolytic degradation of their apolipoprotein B (apoB) component. This was verified by demonstrating that addition of such peptides to LDL-copper ion mixtures completely prevented oxidation of LDL and that this protective effect could be overcome by adding copper ions in excess. Furthermore, proteolytic degradation of the apoB of LDL, with concomitant release of copper-containing peptides, left the partially degraded apoB without the copper ions necessary for propagation of LDL oxidation. These observations provide the first evidence for cell-mediated inhibition of LDL oxidation.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

To further understand the factors involved in the regulation of high plasma triglyceride (TG) or low plasma high density lipoprotein cholesterol (HDL-C) levels, three groups of male subjects (normal TG with low HDL-C levels, high TG with normal HDL-C levels, and high TG with low HDL-C levels) were compared with a sample of normolipemic men with normal TG and HDL-C plasma levels. Mean age was 34 years (range, 20-42 years), and none of the subjects had plasma TG levels >4.0 mmol/1 or familial hypercholesterolemia. Both groups of subjects with high TG levels had a higher body mass index, waist circumference, waist-to-hip circumferences ratio, and a higher ratio of abdominal to femoral adipose tissue areas as measured by computed tomography when compared with normolipemic control subjects. However, during an oral glucose tolerance test only high TG-low HDL-C men had fasting hyperinsulinemia and higher plasma insulin levels compared with normolipemic subjects. In addition, the high TG-low HDL-C group showed reduced HDL apoprotein (apo) A-I levels and a low HDL2-C/HDLrC ratio. These changes were observed along with a nonsignificant trend for a lower plasma postheparin lipoprotein lipase activity. However, among subjects with high TG and normal HDL-C levels, no evidence of insulin resistance or of a reduction in postheparin lipoprotein lipase activity was observed, suggesting that the high plasma TG levels could be attributed to an increased production of apo B-containing lipoproteins, as high plasma apo B and low density lipoprotein (LDL)-apo B levels were observed in this group. In addition, HDL-apo A-I levels measured in the high TG-normal HDL-C group were similar to normolipemic control subjects. Finally, in men with normal plasma TG and low HDL-C levels, no evidence of insulin resistance was noted, nor was there any sign of reduction in plasma postheparin lipoprotein lipase activity. However, HDL 2 -C, HDL,-C, and HDL-apo A-I levels were reduced, suggesting altered synthesis or catabolism of apo A-I. A nonsignificant trend for increased hepatic TG lipase activity was also observed in both groups with low HDL-C levels. These results provide further support for the presence of metabolic heterogeneity underlying high plasma TG or low HDL-C concentrations in men.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

High levels of very low density lipoprotein triglycerides and low levels of high density lipoprotein cholesterol have been found to be associated with insulin resistance measured by the euglycemic clamp technique. In contrast, the association of isolated hypercholesterolemia with insulin resistance has not been systematically studied. Therefore, we performed two separate studies designed to investigate the degree of insulin resistance in familial hypercholesterolemia (FH) (study 1) and nonfamilial hypercholesterolemia (non-FH) (study 2). Study 1 included eight young adults with FH and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were similar in FH patients and control subjects during an oral glucose tolerance test. During the euglycemic hyperinsulinemic (1,200- 1,300 pmol/1) clamp studies, FH patients and control subjects had similar rates of whole-body glucose uptake (73±6 versus 70±3 /unol/kg per minute, respectively;p=NS). Glucose oxidation, glucose nonoxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. Study 2 included 25 middle-aged non-FH patients and 18 corresponding control subjects. Glucose, insulin, and C-peptide responses in an oral glucose tolerance test were similar in both groups. During the euglycemic hyperglycemic clamp studies, non-FH patients and control subjects had similar rates of whole-body glucose uptake (61±3 versus 58±3 /tmol/kg per minute,p=NS). In addition, glucose oxidation, glucose nonoxidation, lipid oxidation, and suppression of free fatty acid levels as well as potassium disposal were similar in non-FH patients and control subjects. We conclude that FH and non-FH are not insulin-resistant states.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Binding of plasmin (ogen) to rat C6 glioma cells is saturable and kringle-domain dependent. This interaction was studied as a model of plasimin(ogen) receptor interactions in nucleated mammalian cells. Apparentl25I-plasmin dissociation from OS cell binding sites was slow; however, the dissociation rate was increased when the solution contained diisopropyl phosphoryl-plasmin (0.3 juM), fibrinogen (0.16 or 0.8 mg/ml), 1.08 mM D-Val-L-Leu-L-Lys-p-nitroanilide-HCl (S-2251), or e-amino-n-caproic acid (EACA, 5.0 mM). EACA promoted the most rapid dissociation of plasmin. C6 cell-associated plasmin and plasmin in solution demonstrated similar amidase activity. Only specifically bound plasmin (75% of total binding) was active against S-2251. Plasmin that was initially bound to C6 cells digested fibrinogen in a timeand plasmin concentration-dependent manner. α-Antiplasmin (α2AP, 0.1fiM)completely inhibited fibrinogenolysis by plasmin that was initially C6 &#149; or human umbilical vein endothelial-cell associated. Sincea2APreacts selectively with plasmin in solution (minimally with plasmin bound to cells), fibrinogen digestion by cell-associated plasmin probably occurred only after the plasmin dissociated into solution. Crosslinked fibrin clots were formed in uniform layers over C6 cells. If the cells were incubated with plasmin before addition of fibrinogen and thrombin, the clots were rapidly lysed. α2AP incompletely inhibited fibrinolysis when added after fibrin polymerization (44% inhibition with 0.1 μM or α2AP). Fibrinolysis was completely inhibited when t$AP was added before fibrin polymerization. These studies suggest that plasmin must first dissociate from cellular binding sites to mediate fibrinogenolysis or fibrinolysis. After dissociation, plasmin activity is modulated by antiplasmins, which are ineffective at the cell surface.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

A group of 200 patients with familial hypercholesterolemia (FH) who were attending lipid clinics in the London area have been screened for four known point mutations and a microdeletion in exon 4 of the low density lipoprotein receptor gene by polym erase chain reaction (PCR) amplification of genomic DNA and either enzyme digestion of the product or hybridization with allele-specific oligonucleotides. A point mutation of Ser,$−>Leu that was initially described in a Puerto Rican family was found in one patient of Polish origin on a different haplotype from that described originally and thus is likely to have occurred independently. A 3-bp deletion that causes deletion of amino acid Gly,197was found in six of the patients, who were all of Jewish origin and who shared the same haplotype for the mutant allele. A mutation of Asp206−*Glu that has been described in the Afrikaner population was found in three patients, two of UK origin and one a recent immigrant from South Africa. In all cases the haplotype of the mutant allele was compatible with that described in the original patient The mutations at Asp$ reported in South African patients and atGμ2tnreported in French Canadian patients were not detected in this sample. However, two additional mutations have been identified in this sample: the first, a 2-bp deletion in codon 206 that was found in five patients, all of British ancestry, and the second, a point mutation in a single patient of Irish origin that creates a stop codon at residue Cy,5210. Of the 200 FH patients in the sample, the molecular defect in 16 (8%) could be detected by PCR using three different tests. Thus, based on the results from analysis of exon 4, the data suggest that during screening of FH patients who have been selected from a population of heterogeneous origin, only a limited spectrum of reported mutations will be found and the occurrence of the same mutation in different patients does not necessarily imply that they share a common ancestor, especially for those mutations occurring at 5′-CpG-3′ d.inucleotides.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We studied the association between isolated systolic hypertension (ISH) and generalized atherosclerosis as indicated by intima-media wall thickness (IMT) of the distal common carotid artery. The Rotterdam Elderly Study is a single-center study of a cohort of 11,854 elderly persons >55 years old. Baseline measurements included ultrasonic evaluation of plaques and vessel wall thickness of both carotid arteries and extensive measurements of cardiovascular risk factors. Mean IMT and lumen diameter of subjects with ISH (systolic pressure >160 mm Hg and diastolic pressure <90 mm Hg) among the first 1,000 participants (n=33) and 66 ageand sex-matched control subjects were compared. None of the subjects were using antihypertensive drug treatment, and all were free of cardiovascular disease. Mean IMT of the right common carotid artery was significantly higher in those with ISH than in normotensive subjects, with a mean difference of 0.07 mm (95% confidence interval [CI], 0.01, 0.14). Results for the left carotid artery were similar (mean difference, 0.06 mm; 95% CI, −0.01, 0.13). The end-diastolic mean lumen diameter was significantly larger in subjects with ISH than in control subjects for both right and left sides, with a mean difference of 0.70 mm (95% CI, 0.38, 1.01) and 0.48 mm (95% CI, 0.17, 0.80), respectively. Adjustment for differences in body mass index, serum lipids, smoking, and fibrinogen did not materially change the findings. Furthermore, atherosclerotic plaques were more frequently observed among those with ISH compared with control subjects, with a mean difference of 12% (95% CI, -1, 25). Our findings suggest that generalized atherosclerosis, ultrasonographically determined as increased carotid IMT, is associated with ISH in asymptomatic elderly subjects.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Oxygenation of the arterial wall is provided by diffusion of oxygen outward from the main vessel lumen and inward from the adventitial vasa vasorum. In a group of four Yucatan miniature pigs the oxygenation profiles across the superficial femoral arteries were recorded by polarographic oxygen microelectrodes. The profiles obtained suggested a relatively poorly oxygenated media (a trough value of approximately 25% that of the intimal oxygenation) with a progressive rise in oxygenation toward the intimal and adventitial surfaces. In four other survival experiments, occlusion of the adventitial vasa vasorum by flush ligation of the arterial branches that supply them resulted in the production of a focal, intimal hyperplastic lesion that was absent in control vessels (intimal to medial ratios [mean±SEM] of 0.053±0.008, n=8,p<0.001 and 0.013±0.001,n=8, respectively). By electron microscopy this lesion was seen to be composed mainly of smooth muscle cells. This evidence would support the hypothesis that arterial wall hypoxia may be involved in tllie initiation of intimal hyperplasia. It is proposed that human atherosclerosis may be initiated by occlusion of the vasa vasorum and concomitant hypoxia.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

In this study we evaluated two different""To-labeling techniques to produce "To-low density lipoprotein (99mTc-LDL) suitable for the scintigraphic delineation of experimental atherosclerotic lesions. The two methods are 1) a procedure that uses stamnous chloride and sodium borohydride (borohydride method) and 2) a procedure that uses sodium dithiionite as a reducing agent and that has been successfully applied in previous scintigraphic atherosclerosis; detection (dithionite method). ""Tc-LDL produced by either method was injected into New Zealand White rabbits with diet-induced atherosclerotic plaques and in control rabbits. Scintigraphic images were taken 10 minutes (t=0) and 1, 4, 8, 16, and 24 hours after injection. Clearance of plasma radioactivity was also studied. Stability of the " m Tc-LDL complex in the circulation was examined by size exclusion chromatography of plasma samples. After scintigraphy, the animals were killed, and the biodistribution of radioactivity was determined. The thoracic and abdominal aortas appeared in scintigraphic images to accumulate " m Tc over their entire length with either "Tc-LDL preparation. The sparse imaging of focal atherosclerosis was found to be due to the fact that the aortas were covered with confluent atherosclerotic lesions. Scintigraphic image analysis showed that 24 hours after injection, the accumulated radioactivity in the abdominal aorta of the atherosclerotic rabbits was 57% and 54%, respectively, of the accumulated radioactivity in the abdominal aorta at t=0 when the borohydride versus the dithionite method was used. In the control animals this value was 25% for the dithionite method, whereas in the borohydride method the aortas could not be detected in the images at t=24 hours. When the borohydride method was used, radioactivity in the abdominal aorta in the atherosclerotic animals was significantly higher than in control rabbits 4 hours after injection of the "Tc-LDL. For the dithionite method (his was 16 hours after injection. Plasma radioactivities in atherosclerotic animals at t=24 hours were 28% and 41% of plasma radioactivity at t=0 for the borohydride and the dithionite method, respectively. In control animals these values were 6% and 18%, respectively. Both methods produced relatively stable "Tc-LDL complexes, with 72% and 68% of the """Tc remaining attached to LDL at t=24 hours. In the biodistribution study, uptake of radioactivity in the aortas was comparable for both labeling methods. We conclude that the borohydride method may be useful in the scintigraphic detection of atherosclerosis, since it yields "Tc-LDL that accumulates in atherosclerotic lesions to the same extend as LDL labeled by the dithionite method. In addition, it is cleared from the circulation considerably faster, resulting more rapidly in a higher target-to-nontarget ratio, which facilitates early identification of atherosclerosis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID