摘要:

Hypercholesterolemia, before atherosclerosis, is known to reduce agonist- (e.g., acetylcholine) mediated nitric oxide (NO) production within 2 weeks of a cholesterol-enriched diet. However, no data exist on the effect of hypercholesterolemia on the basal release of NO from blood vessels. We studied the basal release of NO in rabbit coronary arteries by addition of the NO synthase blocker yVG-nltro-L-arginine-methyl ester (L-NAME). Basal release of NO was markedly attenuated 2 weeks after introduction of a 0.5% cholesterol addition to the diet One week later, the adherence of neutrophils to the coronary endothelium was significantly enhanced (i.e., threefold;p<0.01 different from control). The increased adhesiveness could be attributed to enhanced endothelial adhesion rather than to changes in the properties of the leukocytes. Both phenomena could be reversed by addition of L-arginine to isolated coronary arteries. Administration of 10 mg/day lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, markedly attenuated both the reduced basal NO production and the increased adhesiveness of the endothelium. These results support the concept that NO is an important protective agent produced by the endothelium to preserve the integrity of the endothelium and may protect it against atherogenesis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Cigarette smokers, but not former smokers, excrete more thromboxane A2(TxA2) metabolites in the urine than do lifelong nonsmokers, which suggests chronic activation of their platelets. To further characterize the effect elicited by smoking on platelet function, we followed the change in urinary excretion of the 2,3-dinor (Tx-M) and 11-dehydro (dTx) metabolites of TxAj, analyzed by gas chromatography/mass spectrometry and radioimmunoassay, respectively, in eight healthy women who quit habitual smoking and compared it with the recovery of these metabolites after a single dose of acetylsalicylic acid (ASA). Tx-M and dTx before cessation of smoking were approximately 550 and 600 pg/mg creatinine, respectively. Within 3 days after quitting smoking, Tx-M and dTx had dropped to stable levels of approximately 300 and 350 pg/mg, respectively. The rates of change in excretion of Tx-M and dTx after smoking cessation were more rapid (p<0.02 and 0.02, respectively) than those observed during the recovery of platelet function after a single dose of ASA. The excretion of 2,3-dinor-6-keto-prostaglandin ¥la, a metabolite of prostacyclin, was not affected by smoking cessation. We conclude that cigarette smoking elicits an increase in platelet activity in the absence of vascular injury. This increase is reversible within the life span of the platelets.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

In a preliminary 1987 study, we reported that the plasma fibrinogen level was significantly higher in Caucasian American men than Japanese men. To confirm this finding, we used data from 1,020 Japanese men and women in a 1989-1991 Akita, Japan, population study and from > 15,000 men and women from the 1986-1989 Atherosclerosis Risk in Communities (ARIC) Study. To examine further the correlates of plasma fibrinogen level, subsamples of nonsmoking Akita Japanese (n = 150) and Minneapolis Caucasians (n=150) were also studied separately in 1990. Compared with the Japanese in the Akita study, Caucasians and African Americans in ARIC had a 23-40 mg/dL higher age-adjusted fibrinogen level for men and a 25-67 mg/dL higher level for women. In the subsample, the mean plasma fibrinogen value was 288 mg/dL in Caucasian men and 248 mg/dL in Japanese men (test for difference:p<0.001). Women showed a similar racial difference: 300 mg/dL in Caucasians and 257 mg/dL in Japanese (p<0.001). There were weak but positive correlations of plasma fibrinogen with age and body mass index and weak inverse correlations with alcohol intake, high density lipoprotein cholesterol, and triglycerides in most of the sex-race groups. For women, plasma fibrinogen was positively associated with menopause and inversely associated with the use of hormone replacement therapy. Total fish intake was inversely associated with plasma fibrinogen in all sex-race groups, and the association was statistically significant for Caucasian men. After controlling for these correlates, the Japanese-Caucasian difference in mean fibrinogen value was smaller but was not eliminated: mean difference of 23 mg/dL (95% confidence interval, 0-47) for men and of 41 mg/dL (16–67) for women. These results confirm and extend the preliminary finding that plasma fibrinogen level is higher in American than in Japanese populations. This may contribute to the higher rate of coronary heart disease mortality in the United States than Japan.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

5-Nitrosothiols may serve as carriers in the mechanism of action of endothelium-derived relaxing factor (EDRF) by stabilizing the labile nitric oxide (NO) radical from inactivation by reactive species in the physiological milieu and by delivering NO to the heme activator site of guanylyl cyclase. Low-molecularweight thiols, such as cysteine and glutathione, form 5-nitrosothiol adducts with vasodilatory and antiplatelet properties, and protein thiols can interact in the presence of NO and/or EDRF to form uniquely stable 5-nitroso-proteins. We now show that the 5-nitroso-proteins, 5-nitroso-albumin, 5-nitroso-tissue type plasminogen activator, and 5-nitroso-cathepsin B, have potent antiplatelet effects with an ICso of approximately 1.5 fiM. In the dog, 5-nitroso-albumin inhibits ex vivo platelet aggregation and significantly prolongs the template bleeding time from 2.15±0.13 (mean±SEM) to 9.70±1.24 minutes. The antiplatelet action of 5-nitroso-proteins is associated with the stimulation of guanylyl cyclase and a significant decrease in flbrinogen binding to platelets. 5-Nitroso-proteins undergo thiol-nitrosothiol exchange with low-molecular-weight thiols to form low-molecular-weight 5-nitroso-thiols, and they also interact directly with the platelet surface, both of which processes facilitate generation of NO. These data suggest that 5-nitroso-proteins are potent antiplatelet agents and may be intermediates in the antiplatelet mechanism of EDRF action.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Several epidemiological studies have found that the plasma fibrinogen level is a risk factor for ischemic heart disease (IHD), similar in importance to the serum cholesterol level. A family history of IHD is also a significant risk factor for IHD, statistically independent of the serum cholesterol level. Whether the familial risk for IHD is related to genetic control of the fibrinogen level is unknown. Estimates of the genetic contribution to the variance in plasma fibrinogen levels vary markedly. We previously found elevated levels of cholesterol and factor VH in young subjects with a familial history of premature IHD. In the present study we chose to measure fibrinogen, factor VII antigen, and total cholesterol levels in 43 asymptomatic first-degree relatives (<50 years old) of patients with premature IHD and in 43 ageand sex-matched asymptomatic young adults at low risk of IHD. No subjects in either group were smokers. The mean plasma fibrinogen level of the high-risk group (259 mg/dL) did not differ significantly from that of the low-risk group (250 mg/dL; p>0.4). In contrast, the high-risk group had significantly higher mean factor VII antigen (p<0.001) and mean serum cholesterol (p<0.0001) than the low-risk group. These data argue against the hypothesis that genetic determination of the plasma fibrinogen level is a common pathophysiological mechanism responsible for familial risk of IHD.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Postprandial chylomicron remnant clearance was studied in six patients with familial combined hyperlipidemia (FCH) and seven control subjects by using an oral retinyl palmitate (RP) fat-loading test The chylomicron remnant clearance (S,< 1,000 fraction), expressed as the area under the RP curve (AUC-RP), was delayed in FCH subjects (65.05 ±12.84 hours × [mg/L]) compared with control subjects (25.1±5.4 hoursx[mg/L]; p=0.01). Postprandial lipoprotein particle size and composition in the Sf> 1,000 fraction were different between FCH and control subjects as analyzed by molecular-sieve chromatography. Fasting high density lipoprotein cholesterol was lower in FCH patients (0.54 ±0.09 mmol/L) than in control subjects (0.89±0.05 mmol/L;p<0.01). Mean plasma postheparin lipoprotein lipase and hepatic lipase activities were similar between FCH patients (94 ±25 and 427 ±57 milliunits/mL, respectively) and control subjects (126±16 and 362±33 milliunits/mL, respectively). In FCH, a 54% reduction (p<0.05) of plasma triglycerides to 2.63±0.41 mmol/L by drug treatment resulted in an enhanced, but not normalized, clearance of chylomicron remnants (39.4±6.0 hours × [mg/L]). Univariate regression analysis revealed that in FCH subjects the changes in fasting plasma apolipoprotein C-III concentrations after therapy were significantly associated with the changes in chylomicron remnant AUC-RP (r=0.87;p=0.02). Delayed elimination of atherogenic chylomicron remnants may contribute to the increased risk of premature atherosclerosis in FCH.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The relations of cholesteryl ester transfer protein (CETP) activity to the distribution of low density lipoproteins (LDLs) and high density lipoproteins (HDLs) were investigated in fasting plasma samples from 27 normolipidemic subjects. LDL and HDL subtractions were separated by electrophoresis on 20-160 g/L and 40-300 g/L polyacrylamide gradient gels, respectively. Subjects were subdivided into two groups according to their LDL pattern. Monodisperse patterns were characterized by the presence of a single LDL band, whereas polydisperse patterns were characterized by the presence of several LDL bands of different sizes. To investigate the influence of lipid transfers on LDL patterns, total plasma was incubated at 37°C in the absence of lecithin: cholesterol acyltransferase (LCAT) activity. The incubation induced a progressive transformation of polydisperse patterns into monodisperse patterns. Under the same conditions, initially monodisperse patterns remained unchanged. Measurements of the rate of radiolabeled cholesteryl esters transferred from HDL3s to very low density lipoproteins (VLDLs) and LDLs revealed that subjects with a monodisperse LDL pattern presented a significantly higher plasma CETP activity than subjects with a polydisperse LDL pattern (301±85%/hr per milliliter versus 216±47%/hr per milliliter, respectively;p<0.02). In addition, when total plasma was incubated for 24 hours at 37°C in the absence of LCAT activity, the relative mass of cholesteryl esters transferred from HDLs to apolipoprotein B-containing lipoproteins was greater in plasma with monodisperse LDL than in plasma with polydisperse LDL (023±0.06 versus 0.17±0.06, respectively;p<0.02). These results indicated that in normolipidemic plasma, CETP could play an important role in determining the size distribution of LDL particles. The analysis of lipoprotein cholesterol distribution in the two groups of subjects sustained this hypothesis. Indeed, HDL cholesterol levels, the HDL:VLDL+LDL cholesterol ratio, and the esterified cholesterol: triglyceride ratio in HDL were significantly lower in plasma with the monodisperse LDL pattern than in plasma with the polydisperse LDL pattern (p<0.01,p<0.01, andp<0.02, respectively). Plasma LCAT activity did not differ in the two groups. Plasma CETP activity correlated positively with the level of HDLy, (r=0.542,p<0.01) in the entire study population. Whereas plasma LCAT activity correlated negatively with the level of HDL$ (r=−0.455,p<0.05) and positively with the levels of HDL:, (r=0.475,p<0.05) and HDL* (r=0.485,p<0.05), no significant relation was observed with the level of HDLjb. These results suggest that both monodisperse LDL patterns and high levels of HDLj, particles are specific markers of an elevation of CETP activity in normolipidemic plasma.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Elevated mean levels of lipoprotein [a] (Lp[a]) have been associated with symptomatic cardiovascular diseases such as clinically manifest myocardial infarction (MI), coronary artery disease, restenosis of coronary artery vein grafts after bypass, and a family history of MI. Associations of Lp[a] with arterial wall thickening in asymptomatic individuals previously have not been addressed and are evaluated in this report among participants of the Atherosclerosis Risk in Communities (ARIC) Study. Intima-media wall thickening in the extracranial carotid arteries was assessed noninvasively with B-mode ultrasonography, Lp[a] was measured as its total protein component Individuals with wall thickening £9Oth percentile of the population maximum far-wall thickness were pair matched to participants <75th percentile of wall thickness by race, gender, center, 10-year age group, and time of examination. These selection criteria yielded 492 matched pairs, with 395 white pairs and 97 black pairs. The mean Lp[a] protein level for all black participants was 174.6 /ig/mL compared with 77.8 $ig/mL for whites. Conditional logistic regression analysis for the association of Lp[a] with case-control status yielded a statistically significant prevalence odds ratio (OR) estimate of 1.49, based on a 1-SD difference in Lp[a] protein, after adjusting for age, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, hypertension, and cigarette smoking. None of these risk factors significantly altered the OR, in agreement with reports that Lp[a] is unaffected by environmental influences. In addition, no differential effect of Lp[a] protein on case-control status (effect modification) was observed by race, gender, low-density lipoprotein cholesterol, or fibrinogen in this population. We conclude that Lp[a] is an independent risk factor for intima-media carotid thickening in individuals free of prevalent cardiovascular disease. Further investigation of racial effects may benefit from a population-based analysis that includes additional black participants as well as from elucidation of apolipoprotein[a] polymorph differences between races and degree of wall thickening.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The substrate specificity of lipid transfer protein has been examined in whole plasma in vitro by following the redistribution of high density lipoprotein (HDL)-derived [3H] cholesteryl ester (CE) into apolipoprotein (apo) B-containing lipoproteins using density gradient ultracentrifugation. HDL-derived [3H]CEs were incubated with plasma or isolated lipoprotein classes (very low density lipoprotein, intermediate density lipoprotein, and low density lipoprotein [LDL] subpopulations from the HDL donor) with and without lipoprotein lipase for 0.5-6 hours at 37°C. After incubation, lipoproteins were separated into 38 fractions after density gradient ultracentrifugation, and radioactivity, protein, and cholesterol were monitored across the profiles. These studies indicate that 1) lipid transfer protein activity varied among the individuals as well as within an individual; 2) the majority of the [3H]CE was associated with LDL; 3) in most individuals (71%), more HDL-derived [3H]CE distributed within the buoyant LDL density region; and 4) the distribution of HDL-derived [3H]CE was similar to the distribution of lipoprotein lipase-derived "remnant" particles within buoyant LDL. These in vitro studies support the hypothesis that HDL-derived [3H]CEs vary in their distribution among apo B-containing particles and that more HDL-derived [3H]CEs are transferred to lipoproteins within the buoyant LDL density range. Additional studies suggest that lipoprotein heterogeneity within this density range, such as the presence of remnant-like lipoproteins, may contribute to the selective distribution of HDL-derived [3H]CE into buoyant LDL.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Reduced plasma levels of high density lipoprotein (HDL) cholesterol are associated with increased risk for coronary heart disease. Although plasma HDL levels are, in general, inversely related to plasma triglyceride (TG) concentrations, a small proportion of individuals with low HDL cholesterol concentrations have normal plasma TG levels. We wished to determine whether subjects with low plasma levels of HDL cholesterol could be characterized by common abnormalities of lipoprotein metabolism independent of plasma TGs. Therefore, we studied the metabolism of low density lipoprotein (LDL) apolipoprotein B (apo B) and HDL apolipoprotein A-I (apo A-I) in subjects with low plasma HDL cholesterol concentrations with or without hypertrigh/ceridemia. Nine subjects with low plasma HDL cholesterol levels and normal levels of plasma TGs and LDL cholesterol were studied. AutologousI3II-LDL and12SI-HDL were injected intravenously, and blood samples were collected for 2 weeks. LDL apo B and HDL apo A-I levels were measured by specific radioimmunoassays. Fractional catabolic rates (FCRs, pools per day) and production rates (PRs, milligrams/kilogram - day) for each apolipoprotein were determined. The results were compared with those obtained previously in nine subjects with low plasma HDL cholesterol levels and hypertrigh/ceridemia and in seven normal subjects. The normal subjects had an HDL apo A-I FCR (mean±SD) of 0.21 ±0.04. Despite large differences in plasma TG levels, the HDL apo A-I FCRs were similar in the low-HDL, normal-TG group (0 JO±0.09) and the low-HDL, high-TG group (0J3±0.10), although only the latter value was significantly increased versus control subjects (p< 0.03). Increased apo A-I FCRs were associated with reduced HDL apo A-I levels in both groups of patients. Apo A-I PRs were similar in all groups. In contrast, LDL apo B PR was increased approximately 50% in the low-HDL, normal-TG group (193±6.6;p<0.01) compared with normal subjects (12.5±2.6). There was a strong trend toward a greater LDL apo B PR in the low-HDL, high-TG group (17.6±4.5;p=0.06 versus normal subjects) as well. LDL apo B FCRs were similar in all three groups. LDL apo B concentrations were also increased in the group with low HDL cholesterol and normal TG levels. Both groups with low HDL cholesterol levels had cholesterol-depleted LDL and HDL particles. In summary, reduced levels of plasma HDL cholesterol were generally associated with accelerated fractional removal of HDL apo A-I from plasma, increased production of plasma LDL apo B, and evidence of increased cholesteryl ester transfer out of LDL and HDL. The presence of these similar metabolic abnormalities whether or not plasma TG levels were increased suggests that increased apo B production may be a central defect in these patients and that low plasma HDL levels may be closely linked to increased plasma levels of apo B-containing lipoproteins independent of circulating levels of plasma TG.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID