Cholesterol In Arterial Walls Research Articles

Dietary phytosterol does not accumulate in the arterial wall and prevents atherosclerosis of LDLr-KO mice

ScopeThere have been conflicting reports on the usefulness of phytosterols (PS) in preventing atherosclerosis. We evaluated the effects of dietary PS supplementation in LDLr-KO male mice on the plasma and aorta sterol concentrations and on atherosclerotic lesion development. Methods and resultsMice were fed a high fat diet (40% of energy) supplemented with or without PS (2% w/w, n = 10). Plasma and arterial wall cholesterol and PS concentrations, lesion area, macrophage infiltration, and mRNA expression from LOX-1, CD36, ABCA1 and ABCG1 in peritoneal macrophages were measured. After 16 weeks, the plasma cholesterol concentration in PS mice was lower than that in the controls (p = 0.02) and in the arterial wall (p = 0.03). Plasma PS concentrations were higher in PS-fed animals than in controls (p < 0.0001); however, the arterial wall PS concentration did not differ between groups. The atherosclerotic lesion area in the PS group (n = 5) was smaller than that in controls (p = 0.0062) and the macrophage area (p = 0.0007). PS correlates negatively with arterial lipid content and macrophage (r = −0.76; p < 0.05). PS supplementation induced lower ABCG1 mRNA expression (p < 0.05). ConclusionsDespite inducing an increase in PS plasma concentration, PS supplementation is not associated with its accumulation in the arterial wall and prevents atherosclerotic lesion development.

Statin safety and chronic liver disease

Coronary atherosclerosis is a major cause of morbidity and mortality in Western society. Deposition of cholesterol in arterial walls is central to the pathogenesis of atherosclerosis. It is therefore understandable that based on extensive evidence, aggressive treatment of dyslipidaemia has become standard practice, especially in high-risk groups. Inhibitors of the liver enzyme hydroxymethyl glutaryl coenzyme A reductase (statins) are the most effective and widely prescribed lipid-modifying agents. In long-term use, statins have proved to be safe and well tolerated, but there remain two areas for concern. The first is that of muscle pain or damage and this has recently been reviewed (1,2). The second concern is about hepatotoxicity, both in normal subjects and in patients with chronic liver disease. There are an increasing number of referrals to both lipid and liver clinics regarding the use of statins in the setting of chronic liver disease and also the cause of elevated liver enzymes in patients who are on statins. In addition, there is growing demand for guidance on the use of lipid-lowering agents in the management of those with mild-to-moderate chronic liver disease and excessive cardiovascular risk. The aim of this article is to clarify current prescribing strategies in these two patient populations.

Endothelial dysfunction, lipid peroxidation and cholesterol level in rabbit arteries: relationship to progressive hypercholesterolemia

The aim of this study was to evaluate the influence of a gradual increase in the plasma total cholesterol concentration and of lipid peroxidation on endothelial function in rabbit arteries. Fifty male New Zealand white rabbits were fed a diet enriched with 0.5% cholesterol and 10% coconut oil and were allocated to one of nine groups (G2 to G10) based on sequential determinations of their plasma total cholesterol concentration (each group covered an interval of 100 mg/dL). The control group (G1) consisted of five rabbits fed a non-supplemented diet. The rabbits were killed at the end of the treatment and the total plasma cholesterol concentration, arterial wall cholesterol level and lipid peroxidation based on the quantification of malondialdehyde were determined using commercial kits. Endothelial function was assessed based on concentration-response curves to acetylcholine and sodium nitroprusside in aortic segments. Treatment with a cholesterol-rich diet resulted in disproportional increases in the arterial wall cholesterol concentration, lipid peroxidation and a disproportional decrease in the maximum endothelium-dependent relaxations in relation to the plasma total cholesterol concentration. However, the maximum endothelium-dependent relaxations were proportional to the increase in the arterial wall content of malondialdehyde. These results show that the levels of arterial wall cholesterol, lipid peroxidation and endothelial dysfunction are not proportional to the degree of hypercholesterolemia, although endothelial dysfunction is proportional to the extent of lipid peroxidation in the vessel wall. El objetivo de este estudio ha sido evaluar la influencia de un aumento gradual en la concentración de colesterol total plasmático y de la peroxidación lipídica sobre la función endotelial en arterias de conejo. Cincuenta conejos macho New Zealand fueron alimentados con una dieta enriquecida en colesterol al 0,5% y un 10% de aceite de coco y fueron distribuidos en nueve grupos (G2 a G10) según las determinaciones secuenciales de sus concentraciones plasmáticas de colesterol (cada grupo cubrió un intervalo de 100 mg/dl). El grupo control (G1) estaba formado por 5 conejos alimentados con una dieta no suplementada. Los animales se sacrificaron al final del tratamiento y la concentración de colesterol total plasmático, los valores de colesterol de la pared arterial y la peroxidación lipídica basada en la cuantificación de los valores de malondialdehído se determinaron utilizando kits comerciales. La función endotelial se valoró utilizando curvas concentración-respuesta a la acetilcolina y a nitroprusiato sódico en segmentos de aorta. El tratamiento con la dieta rica en colesterol causó un aumento desproporcionado en la concentración de colesterol en la pared arterial, la peroxidación lipídica y una reducción desproporcionada en las relajaciones máximas dependientes del endotelio en relación con la concentración plasmática de colesterol total. Sin embargo, las relajaciones máximas dependientes del endotelio fueron proporcionales al aumento en la pared arterial del contenido de malondialdehído. Estos resultados muestran que los valores de colesterol de la pared arterial, la peroxidación lipídica y la función endotelial no son proporcionales al grado de hipercolesterolemia, aunque la disfunción endotelial es proporcional a la extensión de la de la peroxidación lipídica en la pared del vaso.

Arterial wall cholesterol content is a predictor of development and severity of arterial thrombosis

It is unclear if total cholesterol content contributes to the severity of cardiovascular events by affecting the amount of thrombosis. This study evaluated relationships between cholesterol levels and the amount of thrombosis in an atherosclerotic rabbit model of plaque disruption and thrombosis. Three groups of NZW rabbits were used: normal rabbits (Group I, n = 4); atherosclerotic rabbits (Group II, n = 4); and atherosclerotic rabbits with pharmacologically triggered thrombosis (Group III, n = 16). Atherosclerosis was induced by feeding a cholesterol enriched diet and balloon deendothelialization. At post-mortem, platelet-rich thrombus and arterial wall cholesterol were quantified and histology performed by light and electron microscopy. Arterial wall cholesterol was strongly correlated to serum cholesterol in all groups (r = 0.94, p < 0.0001). There was a significant correlation between the thrombus surface area with arterial wall cholesterol in Group III (r = 0.71, p < 0.002). Serum cholesterol, arterial wall cholesterol, and thrombus surface area were all significantly correlated but only arterial wall cholesterol was an independent predictor of thrombosis. A threshold specific for this model was noted for serum and arterial cholesterol levels above which thrombosis consistently occurred. Arterial wall cholesterol was strongly correlated to serum cholesterol and thrombosis severity. Serum cholesterol, arterial wall cholesterol and thrombus surface area were all integrally related.A model of plaque disruption and thrombosis was used to demonstrate a correlation between serum and arterial wall cholesterol (r = 0.94; p < 0.0001); arterial wall cholesterol and the amount of thrombosis (surface area; r = 0.71, p < 0.002). A threshold of serum and arterial cholesterol was determined at which thrombosis occurred in this model.

Cranberry Flavonoids, Atherosclerosis and Cardiovascular Health

Atherosclerosis is the deposition of plaques containing cholesterol and lipids in arterial walls. Atherosclerosis causes cardiovascular disease that lead to heart attacks and stroke. Mortality from these diseases is the leading cause of death in the U.S. Atherogenisis starts with the uptake of oxidized LDL by endothelial macrophages, the accumulation of foam cells in the intima of the artery and the formation of fatty streaks. Research indicates that consumption of flavonoids in foods and beverages may decrease the risk of atherosclerosis. In vitro and in vivo experiments with flavonoids demonstrate that flavonoids are dietary antioxidants and inhibit LDL oxidation, inhibit platelet aggregation and adhesion, inhibit enzymes involved in lipid and lipoprotein metabolism that affect the immune response to oxidized LDL and their uptake by endothelial macrophages, may induce endothelium–dependent vassorelaxation, and may increase reverse cholesterol transport and decrease total and LDL cholesterol. Cranberries contain both hydroxycinnamic acids and flavonoids. The cranberry flavonoids belong to three groups: anthocyanins, flavonols, and proanthocyanidins. This article reviews the literature on the effects of flavonoids on atherosclerosis with an emphasis on the potential effects of the flavonols and proanthocyanidins in cranberries.

Apolipoprotein AI efficiently binds to and mediates cholesterol and phospholipid efflux from human but not rat aortic smooth muscle cells.

Aortic smooth muscle cells (SMC) from several animal species have been reported to resist depletion of cellular cholesterol by the major apolipoprotein of HDL, apoAI. Resistance of SMC to this protective action of apoAI, if present in humans, could contribute to the overaccumulation of arterial wall cholesterol seen in atherosclerosis. We investigated the ability of human aortic medial SMC to bind and be depleted of cholesterol and phospholipids by apoAI. In contrast to rat aortic SMC, but similar to human fibroblasts, human SMC were readily depleted of cholesterol by apoAI, measured by a marked depletion of intracellular cholesterol available for esterification, and an increase in cholesterol efflux to the medium. Human SMC were also actively depleted of the phospholipids phosphatidylcholine and sphingomyelin by apoAI. In contrast, rat SMC released only a small fraction of these cellular phospholipids to apoAI-containing medium. (125)I-labeled apoAI bound with high affinity and specificity to human SMC, but failed to bind to rat SMC. Similar levels of expression of class B, type I scavenger receptor (SR-BI) and caveolin in human and rat SMC suggested these proteins do not account for the differences in apoAI binding or lipid efflux seen in these cells. An enhancer of apolipoprotein-mediated cholesterol efflux, tyrosyl radical-oxidized HDL, markedly amplified the depletion of cholesterol available for esterification in human SMC compared to HDL, but had no enhanced effect in rat SMC. These results show that human SMC bind and are readily depleted of cellular lipids by apoAI, and suggest that apoAI-mediated cholesterol efflux from arterial SMC may contribute significantly to the circulating pool of HDL cholesterol in vivo. The marked difference in apoAI binding to human and rat arterial SMC provides an excellent model to study the nature of the apoAI-cell binding interaction.

Arterial injury by cholesterol oxidation products causes endothelial dysfunction and arterial wall cholesterol accumulation.

Cholesterol oxidation products (ChOx) have been reported to cause acute vascular injury in vivo; however, the pharmacokinetics of ChOx after administration and the mechanisms by which they cause chronic vascular injury are not well understood. To further study the pharmacokinetics and atherogenic properties of ChOx, New Zealand White rabbits were injected intravenously (70 mg per injection, 20 injections per animal) with a ChOx mixture having a composition similar to that found in vivo during a 70-day period. Total ChOx concentrations in plasma peaked almost immediately after a single injection, declined rapidly, and returned to preinjection levels in 2 hours. After multiple injections, the ChOx concentrations rose gradually to levels 2- to 3-fold above baseline levels, increasing mostly in the cholesteryl ester fraction of LDL and VLDL. Rabbit serum and the isolated LDL/VLDL fraction containing elevated ChOx concentrations were cytotoxic to V79 fibroblasts and rabbit aortic endothelial cells. At the time of killing, cholesterol levels in the aortas from ChOx-injected rabbits were significantly elevated despite the fact that plasma cholesterol levels remained in the normal range. In addition, aortas from the ChOx-injected rabbits retained more 125I-labeled horseradish peroxidase, measured 20 minutes after intravenous injection. Transmural concentration profiles across the arterial wall also showed increased horseradish peroxidase accumulation in the inner half of the media from the thoracic aorta in ChOx-injected rabbits. In conclusion, ChOx injection resulted in accumulation of circulating ChOx and induced increased vascular permeability and accumulation of lipids and macromolecules. This study reveals that even under normocholesterolemic conditions, ChOx can cause endothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation, parameters believed to be involved in the development of early atherosclerotic lesions.

Reduction of Intimal Hyperplasia by Naroparcil, a 4-Methylumbelliferyl β- d -Xyloside Analogue, After Arterial Injury in the Hypercholesterolemic Rabbit

4-Methylumbelliferyl beta-D-xylosides (beta-D-xylosides) inhibit proteoglycan synthesis, and this is associated with reduced proliferation and extracellular matrix production by vascular smooth muscle cells. This study evaluated whether treatment with naroparcil, a beta-D-xyloside analogue, reduced intimal hyperplasia after arterial injury in the hypercholesterolemic rabbit. Forty-two rabbits were assigned to three groups that received either a 1% cholesterol-enriched diet (group 1, n = 15) or the same diet with added 100 mg.kg-1 naroparcil (group 2, n = 15) or 300 mg.kg-1 naroparcil (group 3, n = 12). All animals underwent iliac artery endothelial abrasion at day 14 and were killed at day 56. At the time of death, the angiographic minimal luminal diameter was significantly larger in both treated groups. Morphometric analysis showed a larger luminal area in treated rabbits (groups 2 and 3) compared with control rabbits (group 1) (0.75 +/- 0.54 and 0.85 +/- 0.61 mm2 versus 0.32 +/- 0.25 mm2, respectively; P < .05), with a decreased intimal thickness in groups 2 and 3 (average reduction of 37% and 39%, respectively, compared with group 1; P < .05) but without changes in medial area. Total vessel area was comparable among all groups. In the media, immunohistochemistry suggested reduced infiltration by macrophages and a larger fractional area of smooth muscle cells. There were no differences in plasma or arterial wall cholesterol content between groups. Plasma levels of glycosaminoglycans and dermatan sulfate content were increased only in group 3. In this model, oral treatment with naroparcil appears to preserve the arterial lumen and reduce intimal thickness after arterial injury.

Evidence for lipid regression in humans in vivo performed by 123iodine-low-density lipoprotein scintiscanning.

Radiolabeling of autologous LDL allows in vivo characterization of arterial wall lipid metabolism and LDL receptor imaging. Different kinetic types of arterial wall LDL entry reflect the de-, re-, and endothelialized segments in both animals and humans. In 36 male cholesterol-fed rabbits being treated with the calcium channel blocker isradipine (0.3 mg/kg daily), the retention of the radiolabeled (125I-LDL) was reduced, being related to the reduction in arterial wall cholesterol ester content and the decreased extent of Sudan III-positive areas. In parallel, a significant (p < 0.01) increase in vascular prostaglandin I2 (PGI2) generation was seen in endothelialized and reendothelialized segments of the abdominal aorta. These effects were completely abolished by concomitant treatment with acetylicsalicylic acid (ASA). These data could be confirmed in humans, too: a 4-week treatment with prostaglandin E1 (PGE1:5 ng/kg/min iv, 5 days/week, 6 h/day for 6 weeks) and isradipine (2 x 2.5 mg po daily for 4 weeks) did not change arterial 123I-LDL influx kinetics, which were examined over a total of 60 (PGE1) and 96 (isradipine) vascular regions. In contrast to this, the retention of the tracer was significantly diminished in different arterial segments. In isradipine-treated patients, 20 hours after reinjection of radiolabeled LDL, the quantitative LDL entry was reduced by at least 4.7% with a maximum of 23.5% (p < 0.01) in type I (n = 50 lesions) or type II lesions (n = 41). PGE1 treatment induced a 16.9% to 30.7% (p < 0.01) decrease of LDL retention in type I (n = 36 lesions) or type II lesions (n = 24), respectively. These findings support the hypothesis derived from earlier experimental studies that the antiatherosclerotic effects are likely to be due to the increase in PGE1 and/or PGI2 availability mediated by an increase in cAMP. The results demonstrate the potential of 123I-LDL scintigraphy for the characterization of vascular LDL kinetics and the monitoring of functional lipid lesion regression.

Role of plasma lipoproteins in the pathogenesis of atherosclerotic disease, with special reference to sex hormone effects

Plasma lipoproteins constitute a complex lipid transport system. Very low-density lipoproteins transport triglycerides to peripheral tissues, whereas low-density lipoproteins are the main carriers of cholesterol. Cholesterol transported in low-density lipoprotein enters body cells by way of the "low-density lipoprotein receptor pathway" but may also be taken up by macrophages by way of the "scavenger pathway." Excessive influx of cholesterol by way of the "scavenger pathway" may result in deposition of cholesterol in arterial walls and atheroma formation. In a yet incompletely known process of "reverse cholesterol transport," cholesterol is carried away from the tissues to the liver by high-density lipoproteins. The above-mentioned transport processes are regulated by a well-synchronized system that involves several enzymes and lipid transport proteins. Under normal conditions, the lipoprotein system is able to balance the flow of cholesterol and other lipids in both directions between the liver and peripheral tissues. This delicate balance may be disturbed by many factors, including contraceptive steroids. The metabolic steps influenced by administration of contraceptive steroids are summarized. (AMJ OBSTET GVNECOL 1990; 163:296-304.)

The beta-receptor, atheroma and cardiovascular damage

In man a close interrelationship exists between hyperadrenergic states, myocardial ischemia, necrosis, infarction and sudden cardiac death. Persistent high catecholamine levels may also be associated with increased vascular endothelial turnover and permeability to calcium and lipoproteins, increased blood velocity, abnormal blood flow patterns and atheroma formation. There are thus good reasons to predict a cardiovascular protective effect of beta-blockers. Animal data indicate that in spite of apparently adverse plasma lipoprotein changes beta-blockers retard atheromatous plaque formation under conditions of high cholesterol diet with or without stress. A slow heart rate, as well as a reduction in calcium influx and inhibition of both esterification of arterial wall cholesterol (by ACAT) and endothelial permeability to lipoproteins, may be central to this process. Beta-blockers benefit a spectrum of conditions related to the atheromatous process and myocardial necrosis. These are silent ischemia; stable (including mixed), unstable and preinfarction angina; periinfarction events (including myocardial rupture and dissection of the ascending aorta); and myocardial necrosis associated with stress conditions such as head injuries and subarachnoid hemorrhage. In one study coronary deaths in hypertensive men, particularly in smokers, were significantly reduced by metoprolol (a beta 1-selective blocker) compared to a diuretic. In contrast in the MRC study of mild hypertension only nonsmoking men with mild to moderate hypertension who received a nonselective beta-blocker appeared to experience fewer myocardial infarctions. Recent clinical data showed that moderate-severe hypertensives who were optimally controlled by atenolol-based treatment over a 10-year period were less likely to die from myocardial infarction than those suboptimally controlled, irrespective of a rise in serum triglyceride levels. Thus the net effect of acute beta-blockade in hyperadrenergic states, including myocardial infarction, is to limit cardiovascular damage. Chronic beta-blockade inhibits atheroma formation (in animals) and beneficially modifies the incidence of stroke and myocardial infarction, which in man are the long-term consequences of hypertension.

Probucol, high-density lipoprotein metabolism and reverse cholesterol transport

Accumulation of cholesterol within the arterial wall reflects an imbalance between delivery and efflux. Monocyte-derived macrophages play a major role in arterial wall cholesterol accumulation. Using tracer methodology in a rabbit model, several investigators have estimated the rate of cholesterol delivery and thus the steady-state rate of efflux to be between 0.4 and 2.4 micrograms/cm2/hour. The process responsible for arterial wall cholesterol efflux, "reverse cholesterol transport," can be conceptualized as a sequence of events including (1) loss of cell cholesterol, (2) intravascular cholesterol transport, (3) hepatic cholesterol uptake, and (4) biliary secretion. Work by many investigators has characterized these individual processes.

動脈壁の脂質代謝

The following themes were described about the relationship between lipid metabolism and lipid accumulation in arterial wall.1. Introduction of metabolism in arterial wall(1) Lipid metabolism(2) Protein metabolism(3) Glucose metabolism2. Lipoprotein metabolism in arterial wall(1) Lipoprotein and arterial wall(2) Lipoprotein and lipid accumulation3. Cholesterol metabolism in arterial wall(1) Cholesterol ester metabolism in lysosomes(2) Cholesterol ester metabolism in microsomes4. Phospholipid metabolism in arterial wall5. Triglyceride metabolism in arterial wall6. Free fatty acid metabolism in arterial wall7. Lipoperoxide in arterial wall8. Risk factors and lipid metabolism in arterial wall(1) Thrombosis and lipids(2) Hormone and lipid metabolism(3) Hypertension and lipid metabolism9. Regression of atherosclerosis

Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia

The influence of clofibrate on cholesterol metabolism in patients with hyperlipidemia was studied by means of sterol balance and isotope kinetic techniques and by measurements of flow rates of cholesterol through the biliary tract. Long-term balance studies were carried out on a metabolic ward in 24 patients with all currently recognized types of hyperlipidemia; in five other patients with hypercholesterolemia, pool sizes and turnover rates of cholesterol were defined by compartmental analysis before and after three years' daily administration of the drug. Except in fat-induced hypertriglyceridemia (two patients), clofibrate caused reduced plasma levels of triglycerides and cholesterol in all categories of hyperlipidemia. As a general rule, excretion of cholesterol into bile and feces was significantly increased and fecal bile acid excretion was decreased, regardless of the type of lipoprotein abnormality. Despite a net increase in steroid excretion in most patients with hyperlipidemia, cholesterol synthesis was not increased; indeed, in many patients synthesis appeared to be decreased. While the data obtained in 29 patients were not always consistent, the bulk of the evidence suggests that, in all forms of hyperlipidemia except fat-induced hyperglyceridemia, the drug causes an increased output of cholesterol while simultaneously inhibiting any compensatory increase in cholesterol synthesis. Therefore, it appeared that the increased excretion of steroids was most likely derived from cholesterol stored in tissues. This conclusion was strengthened by finding that long-term administration of the drug can cause marked reduction in body pools of cholesterol. These findings are reflected clinically by resolution of skin and tendon xanthomatosis. However, it is not yet known whether the accumulation of cholesterol in arterial walls that is part of the process of atherogenesis can be inhibited or reversed by the drug.

Atherosclerosis and levels of serum cholesterol in postmortem investigations

In our work we have compared the postmortem findings in material from the Forensic Institute in Cracow (persons who died suddenly from various causes) with the levels of cholesterol and the intensity and localization of atherosclerotic lesions. The total content of cholesterol in the serum was determined in 106 cases. Microscopically, examinations were made in 43 cases. The free cholesterol in atherosclerotic alterations was also investigated by the digitonin method. It was confirmed that the average level of cholesterol in individuals suffering from atherosclerosis (240 mg. per cent) is higher than that in those without atherosclerotic symptoms (205 mg. per cent). These differences are statistically significant only in the group of cases of advanced atherosclerosis (260 mg. per cent) and in the group of cases of sudden death from coronary sclerosis (261 mg. per cent). No significant statistical difference was found in the other groups, which differed from each other only in the degree of atherosclerotic changes. The average level of serum cholesterol in people who died from cardiac infarction (238 mg. per cent) was lower than the level of cholesterol in the whole group of persons who suffered sudden coronary death. Microscopic examinations gave no basis for binding conclusions. Also, no relationship was found between the free cholesterol in arterial walls and the total cholesterol in blood serum. The results of these examinations do not differ practically from the results obtained in analogous examinations in health and disease with atherosclerosis, conducted by the same methods, in the same laboratory, and in the same populations.