Reperfusion-induced changes in capillary perfusion and filtration: effects of hypercholesterolemia.
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Fluid filtration rate (J(v)/S) and red blood cell velocity (V(RBC)) in individual mesenteric capillaries of normocholesterolemic (NC) and hypercholesterolemic (HC) rats were measured before and after ischemia and reperfusion (I/R). In NC rats, a correlation was found between baseline J(v)/S and the percent of the feeding arteriole length that was paired (<15 micrometer) with a postcapillary venule (A-V pairing), but not in the HC group. Additionally, in NC rats only, a correlation was found between baseline V(RBC) and A-V pairing. In capillaries in which A-V pairing was substantial (>20%), V(RBC) dropped after reperfusion in the HC group (54% of baseline; P < 0.05), but not in the NC group (79%). The decrease in V(RBC) in HC rats could be attenuated by a P-selectin antibody (PB1.3). PB1.3 was also able to attenuate the increase in I/R-induced capillary J(v)/S in HC rats (median increase = 1.26-fold vs. 1.53-fold without PB1.3). These data suggest a role for A-V pairing in capillary perfusion in NC rats and a potential role for P-selectin in I/R-induced microvascular dysfunction in HC rats. (+info)
Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study.
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BACKGROUND: Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir. METHODS AND RESULTS: Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir. CONCLUSIONS: Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established. (+info)
Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo : possible mechanisms for gender differences in atherosclerosis.
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The mechanism by which estrogens protect against atherosclerosis is not known. We evaluated in vivo whether there is a gender difference in monocyte adhesion and subendothelial migration in hypercholesterolemic rabbits and whether any gender differences observed are due to estradiol. Monocyte adhesion and subendothelial migration were assessed in a blinded fashion by analyzing a standardized segment of aorta using a scanning electron microscope. We also assessed whether estradiol modulates induction of vascular cell adhesion molecule-1 (VCAM-1) protein using Western blot and flow cytometric analyses. We observed that male rabbits develop more monocyte adhesion and subendothelial migration than do female rabbits during hypercholesterolemia. We also observed that oophorectomized rabbits given physiological estradiol supplementation demonstrate fewer adherent and subendothelial monocytes than do oophorectomized rabbits given placebo. VCAM-1 protein expression was increased in aortae obtained from hypercholesterolemic, oophorectomized animals supplemented with placebo, and this increase was attenuated by estradiol. Finally, in cultured rabbit aortic endothelial cells stimulated with lysophosphatidylcholine, we observed an increase in VCAM-1 protein that was inhibited in a concentration-dependent fashion by estradiol. We have demonstrated in vivo that there is a gender difference in monocyte adhesion to endothelial cells and transendothelial migration after hypercholesterolemia and that this gender difference is due in part to estradiol. Our results also suggest that estradiol inhibits monocyte adhesion by inhibiting expression of VCAM-1. (+info)
Dietary taurine enhances cholesterol degradation and reduces serum and liver cholesterol concentrations in rats fed a high-cholesterol diet.
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The effect of taurine on hypercholesterolemia induced by feeding a high-cholesterol (HC) diet (10g/kg) to rats was examined. When various amounts of taurine (0.25, 0.5, 1, 2.5, 5, 10, 20, 30, 40 or 50 g/kg diet) were supplemented to HC for 2 wk, serum total cholesterol gradually and significantly decreased in a dose-dependent manner and normalized at the dose of 10 g taurine/kg, compared with the control (cholesterol free) diet group. By contrast, serum HDL-cholesterol was elevated by taurine supplementation. The HC diet caused a significant decrease in the concentration of taurine in serum, liver and heart compared to that in the control group, and the effective dose of supplemental taurine to improve its reduction was 2.5 g/kg diet. In the hypercholesterolemic rats fed the HC diet, the excretion of fecal bile acids and hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) activity and its mRNA level increased significantly, and the supplementation of taurine further enhanced these indexes, indicating an increase in cholesterol degradation. The abundance of mRNA for Apo A-I, one of the main components of HDL, was reduced by HC and recovered by taurine supplementation. Agarose gel electrophoresis revealed that, in hypercholesterolemic rats fed the HC diet, the serum level of the heavier VLDL increased significantly, but taurine repressed this increase and normalized this pattern. Significant correlations were observed between the time- and dose-dependent increases of CYP7A1 gene expression and the decrease of blood cholesterol concentration in rats fed the HC diet supplemented with taurine (time, r = -0.538, P < 0.01, n = 32; dose, r = -0.738, P < 0.001, n = 20). These results suggest that the hypocholesterolemic effects of taurine observed in the hypocholesterolemic rats fed the HC diet were mainly due to the enhancement of cholesterol degradation and the excretion of bile acid. (+info)
Cholesterol and long-term mortality after acute myocardial infarction in elderly patients.
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METHOD: We investigated the association of total serum cholesterol concentrations and subsequent overall and coronary mortality in 304 patients aged > or =65 discharged from hospital after acute myocardial infarction. RESULTS: There was no association between total cholesterol concentrations and mortality due to either coronary heart disease or to all causes in all patients or, separately, in men, women, patients younger than 75 and patients aged 75 years and older. (+info)
Effect of dietary taurine on endogenous hypercholesterolemia in rats fed on phenobarbital-containing diets.
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The effect of dietary taurine on endogenous hypercholesterolemia induced by a phenobarbital-containing diet was investigated. Supplemented taurine did not affect the concentrations of serum cholesterol, but further potentiated the accumulation of hepatic cholesterol in the hypercholesterolemic state induced by phenobarbital. It is suggested that taurine might amplify the hepatic cholesterogenesis in phenobarbital-induced hypercholesterolemia. (+info)
Cholesterol oxidation products induce vascular foam cell lesion formation in hypercholesterolemic New Zealand white rabbits.
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Circulating cholesterol oxidation products (ChOx) have long been implicated in the etiology of early atherosclerosis; however, direct in vivo evidence elucidating their role in atherogenesis is only recently becoming available. This study investigated ChOx effects on vascular lesion formation in New Zealand White rabbits under controlled hypercholesterolemic conditions. By closely monitoring plasma cholesterol levels and adjusting dietary cholesterol intake during a 78-day period, total plasma cholesterol exposures (cumulative plasma cholesterol levels over time) were controlled between 27 000 and 34 000 mg/dLxday (final plasma cholesterol concentration, 467+/-77 mg/mL), representing a threshold range for sudanophilic lesion formation in the aorta. Twenty injections of a ChOx mixture (70 mg per injection) were made bearing an oxysterol composition similar to that found in circulating oxidatively modified low density lipoprotein. At sacrifice, the ChOx-injected rabbits (n=5) had (1) significantly higher plasma ChOx levels, (2) significantly increased cholesterol content in the aortas, mainly as esterified cholesterol, and (3) significantly greater sudanophilic lesion size and frequency in the aortas compared with vehicle-injected control rabbits (n=5). The aortic cholesterol content and extent of sudanophilic lesion area were correlated significantly with total plasma ChOx exposure (P<0.003 and P<0.0001, respectively) but not with total cholesterol exposure. The results indicate that for moderate experimental hypercholesterolemia, a situation more relevant to physiological hypercholesterolemia in humans, circulating ChOx may play an important role in inducing formation of early atherosclerotic lesions. Because ChOx are often present in cholesterol-containing diets, foam cell lesion formation induced by ChOx rather than cholesterol cannot be overlooked. (+info)
The relative influence of secondary versus primary prevention using the National Cholesterol Education Program Adult Treatment Panel II guidelines.
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OBJECTIVES: This study was undertaken to project the population-wide effect of full implementation of the Adult Treatment Panel (ATP) II guidelines of the National Cholesterol Education Program (NCEP). BACKGROUND: The ATP II has proposed guidelines for cholesterol reduction, but the long-term epidemiologic influence of its components has not been fully examined. METHODS: We used a calibrated, validated simulation of the U.S. population, aged 35 to 84 years to estimate the potential for the NCEP guidelines, under varying assumptions, to reduce coronary heart disease morbidity and mortality and overall mortality from the years 2000 to 2020. RESULTS: Primary prevention would yield only about half of the benefits of secondary prevention despite requiring nearly twice as many person-years of treatment. The projected increase in quality-adjusted years of life per year of treatment for secondary prevention was 3- to 12-fold higher than for primary prevention. To yield population-wide epidemiologic benefits equivalent to NCEP recommendations for secondary prevention, primary prevention would require a nearly sixfold increase in the number of persons treated compared with NCEP recommendations. All benefits of universal success of the NCEP primary prevention "screen and treat" guidelines could be achieved by a 11 mg/dl (8%) population-wide reduction in low-density lipoprotein cholesterol levels among persons without preexisting coronary heart disease. CONCLUSIONS: The NCEP guidelines for targeted primary prevention can be a useful component of a rational public health strategy, but only as a complement to the more appealing strategies of secondary prevention and "across-the-board" programs to lower all cholesterol levels. (+info)