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Plasma high density lipoprotein (HDL), which protects against atherosclerosis, is thought to remove cholesterol from peripheral tissues and to deliver cholesteryl esters via a selective uptake pathway to the liver (reverse cholesterol transport) and steroidogenic tissues (e.g., adrenal gland for storage and hormone synthesis). Despite its physiologic and pathophysiologic importance, the cellular metabolism of HDL has not been well defined. The class B, type I scavenger receptor (SR-BI) has been proposed to play an important role in HDL metabolism because (i) it is a cell surface HDL receptor which mediates selective cholesterol uptake in cultured cells, (ii) its physiologically regulated expression is most abundant in the liver and steroidogenic tissues, and (iii) hepatic overexpression dramatically lowers plasma HDL. To test directly the normal role of SR-BI in HDL metabolism, we generated mice with a targeted null mutation in the SR-BI gene. In heterozygous and homozygous mutants relative to wild-type controls, plasma cholesterol concentrations were increased by approximately 31% and 125%, respectively, because of the formation of large, apolipoprotein A-I (apoA-I)-containing particles, and adrenal gland cholesterol content decreased by 42% and 72%, respectively. The plasma concentration of apoA-I, the major protein in HDL, was unchanged in the mutants. This, in conjunction with the increased lipoprotein size, suggests that the increased plasma cholesterol in the mutants was due to decreased selective cholesterol uptake. These results provide strong support for the proposal that in mice the gene encoding SR-BI plays a key role in determining the levels of plasma lipoprotein cholesterol (primarily HDL) and the accumulation of cholesterol stores in the adrenal gland. If it has a similar role in controlling plasma HDL in humans, SR-BI may influence the development and progression of atherosclerosis

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-dependent transcription factor that has been demonstrated to regulate fat cell development and glucose homeostasis. PPAR gamma is also expressed in a subset of macrophages and negatively regulates the expression of several proinflammatory genes in response to natural and synthetic ligands. We here demonstrate that PPAR gamma is expressed in macrophage foam cells of human atherosclerotic lesions, in a pattern that is highly correlated with that of oxidation-specific epitopes. Oxidized low density lipoprotein (oxLDL) and macrophage colony-stimulating factor, which are known to be present in atherosclerotic lesions, stimulated PPAR gamma expression in primary macrophages and monocytic cell lines. PPAR gamma mRNA expression was also induced in primary macrophages and THP-1 monocytic leukemia cells by the phorbol ester 12-0-tetradecanoylphorbol 13-acetate (TPA). Inhibition of protein kinase C blocked the induction of PPAR gamma expression by TPA, but not by oxLDL, suggesting that more than one signaling pathway regulates PPAR gamma expression in macrophages. TPA induced the expression of PPAR gamma in RAW 264.7 macrophages by increasing transcription from the PPAR gamma 1 and PPAR gamma 3 promoters. In concert, these observations provide insights into the regulation of PPAR gamma expression in activated macrophages and raise the possibility that PPAR gamma ligands may influence the progression of atherosclerosis

In laboratory animals, the consumption of soy protein, rather than animal protein, decreases serum cholesterol concentrations, but studies in humans have been inconclusive. In this meta-analysis of 38 controlled clinical trials, we examined the relation between soy protein consumption and serum lipid concentrations in humans. Methods. We used a random-effects model to quantify the average effects of soy protein intake on serum lipids in the studies we examined and used hierarchical mixed-effects regression models to predict variation as a function of the characteristics of the studies. Results. In most of the studies, the intake of energy, fat, saturated fat, and cholesterol was similar when the subjects ingested control and soy-containing diets; soy protein intake averaged 47 g per day. Ingestion of soy protein was associated with the following net changes in serum lipid concentrations from the concentrations reached with the control diet: total cholesterol, a decrease of 23.2 mg per deciliter (0.60 mmol per liter; 95 percent confidence interval, 13.5 to 32.9 mg per deciliter [0.35 to 0.85 mmol per liter]), or 9.3 percent; low-density lipoprotein (LDL) cholesterol, a decrease of 21.7 mg per deciliter (0.56 mmol per liter; 95 percent confidence interval, 11.2 to 31.7 mg per deciliter [0.30 to 0.82 mmol per liter]), or 12.9 percent; and triglycerides, a decrease of 13.3 mg per deciliter (0.15 mmol per liter; 95 percent confidence interval, 0.3 to 25.7 mg per deciliter [0.003 to 0.29 mmol per liter]), or 10.5 percent. The changes in serum cholesterol and LDL cholesterol concentrations were directly related to the initial serum cholesterol concentration (P 0.001) The ingestion of soy protein was associated with a nonsignificant 2.4 percent increase in serum concentrations of high-density lipoprotein (HDL) cholesterol. Conclusions. We found that the consumption of soy protein rather than animal protein significantly decreased serum concentrations of total cholesterol

Atherosclerosis, an underlying cause of myocardial infarction, stroke, and other cardiovascular diseases, consists of focal plaques characterized by cholesterol deposition, fibrosis, and inflammation. The presence of activated T Iymphocytes and macrophages and high expression of HLA class II molecules are indicative of a local immunologic activation in the atherosclerotic plaque, but the antigen(s) involved has not yet been identified. We established T-cell clones from human atherosclerotic plaques using polyclonal mitogens as stimuli and exposed the clones to potential antigens in the presence of autologous monocytes as antigen-presenting cells. Four of the 27 CD4+ clones responded to oxidized low density lipoprotein (oxLDL) by proliferation and cytokine secretion; this response was dependent on autologous antigen-presenting cells and restricted by HLA-DR. All clones that responded to oxLDL secreted interferon gamma upon activation, but only one produced interleukin 4, suggesting that the response to oxLDL results in immune activation and inflammation but may not be a strong stimulus to antibody production. No significant response to oxLDL could be detected in CD4+ T-cell clones derived from the peripheral blood of the same individuals. Together, the present data suggest that the inflammatory infiltrate in the atherosclerotic plaque is involved in a T-cell-dependent, autoimmune response to oxLDL

Patients with coronary artery disease and abnormalities of serum lipid levels often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilatation is unknown. We randomly assigned 49 patients (mean [+/-SD) serum cholesterol level, 209 +/- 33 mg per deciliter 5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal. Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL-lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P 0.01 for the LDL-lowering-antioxidant group vs. the diet group P

Serum paraoxonase-1 (PON1) binds mainly to high density lipoproteins (HDLs) and protects low density lipoproteins (LDLs) against oxidation. While paraoxonase and arylesterase activities are traditionally assayed, lactonase activity, accounting for protection against LDL oxidation, was less investigated in obese children and adolescents. Therefore, we aimed to measure lactonase, paraoxonase and arylesterase activities, oxidized LDL (ox-LDL) and malondialdehyde (MDA) levels in obese children and adolescents. Study population included 68 children (35 obese and 33 normal-weight). Arylesterase and paraoxonase activities were assayed spectrophotometrically. Lactonase activity, ox-LDL and MDA levels were measured using a pH-sensitive colorimetric assay, an ELISA technique and a fluorimetric method, respectively. The lipid profile was assessed by common methods. Lactonase and arylesterase activities were decreased in the presence of obesity. MDA, but not ox-LDL levels, showed significant differences between groups. Multiple regression analysis identified a reciprocal relationship and a possible association between lactonase and arylesterase activities and obesity.

Cellular and humoral immunity have been implicated in the pathogenesis of atherosclerosis. To determine whether an intact immune system is necessary for the formation of atherosclerotic lesions, we have generated immunodeficient mice with hypercholesterolemia and atherosclerosis by crossbreeding the apolipoprotein E (apoE)-deficient mouse with the recombinase activating gene 1 (Rag-1) knockout mouse. Chow-fed immunodeficient mice with targeted disruption in both apoE and Rag-1 (E0/R0) had a 2-fold decrement in aortic root lesion size at 16 weeks of age, compared with immunocompetent littermates, which were heterozygotes at the Rag-1 locus (E0/R1). Nearly all atherosclerotic lesions from chow-fed animals were limited to raised foam cell fatty streaks. In contrast, when a second group of animals was fed a high-fat Western-type diet to accelerate lesion development, there were no differences in either aortic root lesion size or the percent of the total aorta occupied by lesions. Fibrous plaques with well-defined caps and necrotic cores were detected in both Western diet-fed E0/R0 and E0/R1 animals. We conclude that T and B lymphocytes play only a minor role in the rate of forming foam cell lesions, and they are not necessary for the formation of fibroproliferative plaques.

Background. Dietary plant sterols, especially sitostanol, reduce serum cholesterol by inhibiting cholesterol absorption. Soluble sitostanol may be more effective than a less soluble preparation. We tested the tolerability and cholesterol-lowering effect of margarine containing sitostanol ester in a population with mild hypercholesterolemia. Methods. We conducted a one-year, randomized, double-blind study in 153 randomly selected subjects with mild hypercholesterolemia. Fifty-one consumed margarine without sitostanol ester (the control group), and 102 consumed margarine containing sitostanol ester (1.8 or 2.6 g of sitostanol per day). Results. The margarine containing sitostanol ester was well tolerated. The mean one-year reduction in serum cholesterol was 10.2 percent in the sitostanol group, as compared with an increase of 0.1 percent in the control group. The difference in the change in serum cholesterol concentration between the two groups was -24 mg per deciliter (95 percent confidence interval, -17 to -32; P0.001). The respective reductions in low-density lipoprotein (LDL) cholesterol were 14.1 percent in the sitostanol group and 1.1 percent in the control group. The difference in the change in LDL cholesterol concentration between the two groups was -21 mg per deciliter (95 percent confidence interval, -14 to -29; P0.001). Neither serum triglyceride nor high-density lipoprotein cholesterol concentrations were affected by sitostanol. Serum campesterol, a dietary plant sterol whose levels reflect cholesterol absorption, was decreased by 36 percent in the sitostanol group, and the reduction was directly correlated with the reduction in total cholesterol (r

To develop a murine model system to test the role of monocyte-derived macrophages in atherosclerosis, the osteopetrotic (op) mutation in the macrophage colony stimulating factor gene was bred onto the apolipoprotein E (apoE)-deficient background. The doubly mutant (op/apoE-deficient) mice fed a low-fat chow diet had significantly smaller proximal aortic lesions at an earlier stage of progression than their apoE-deficient control littermates. These lesions in the doubly mutant mice were composed of macrophage foam cells. The op/apoE-deficient mice also had decreased body weights, decreased blood monocyte differentials, and increased mean cholesterol levels of approximately 1300 mg/dl. Statistical analysis determined that atherosclerosis lesion area was significantly affected by the op genotype and gender. The confounding variables of body weight? plasma cholesterol, and monocyte differential, which were all affected by op genotype had no significant additional effect on lesion area once they were adjusted for the effects of op genotype and gender. Unexpectedly, there was a significant inverse correlation between plasma cholesterol and lesion area, implying that each may be the result of a common effect of macrophage colony-stimulating factor levels. The data support the hypothesis that macrophage colony-stimulating factor and its effects on macrophage development and function play a key role in atherogenesis