Oxidized low density lipoprotein inhibits the hemolytic activity of Asp-hemolysin from Aspergillus fumigatus

We have examined the effect of chemically modified human low density lipoproteins (LDLs) , acetylated LDL and oxidized LDL, on the hemolytic activity of Asp-hemolysin. Oxidized LDL, but not acetylated LDL, inhibited the hemolytic activity of this toxin. The inhibitory effects of oxidized LDL increased with the time of Cu²⁺-induced LDL oxidation. Similar inhibition was observed in the filtrate which was separated from the incubation mixture of Asp-hemolysin with oxidized LDL (for 2 h of oxidation) following ultrafiltration through a membrane with a molecular mass cutoff of 100 000. However, at longer LDL oxidation times, the inhibition by the filtrates was less than the control mixture without ultrafiltration. We suggest that the inhibition by oxidized LDL was due to the binding of oxidized LDL to Asp-hemolysin at shorter LDL oxidation times .     

氧化低密度脂蛋白对THP-1巨噬细胞吞噬和分泌功能的影响

目的:探讨氧化低密度脂蛋白(oxidized low density lipoprotein,ox-LDL)对巨噬细胞源性泡沫细胞吞噬功能和炎症相关因子分泌功能的影响。方法:利用佛波酯(phorbol ester,PMA)诱导THP-1细胞分化形成巨噬细胞,之后采用ox-LDL处理48小时后,诱导其形成泡沫细胞。利用中性红吞噬实验,分析泡沫细胞形成前后吞噬功能的变化;通过ELISA法,检测细胞培养上清中肿瘤坏死因子α(tumor necrosis factorα,TNF-α)含量,观察ox-LDL对THP-1巨噬细胞功能的影响。结果:细胞形态学结果表明,我们成功利用ox-LDL诱导THP-1巨噬细胞形成泡沫细胞;进一步发现ox-LDL诱导THP-1巨噬细胞表面的清道夫受体CD36表达升高,并促进细胞吞噬功能增加,进一步促进细胞内胆固醇含量显著升高(P0.05);同时,ox-LDL能够刺激巨噬细胞大量分泌TNF-α(P0.05)。结论:ox-LDL通过增强清道夫受体CD36表达,提高巨噬细胞的吞噬功能,引起大量胆固醇聚集,产生细胞毒性损伤,并促进TNF-α炎性因子的大量分泌。     

Cellular Thiol Production and Oxidation of Low-Density Lipoprotein

Compelling evidence suggests that low-density lipoprotein (LDL) is oxidized by cells within the arterial intima and that, once oxidized, it is profoundly atherogenic. The precise mechanism(s) by which cells promote the oxidation of LDL in vivo are not known; in vitro, however, oxidation of LDL can be enhanced by a number of differing mechanisms, including reaction with free and protein-bound metal ions, thiols, reactive oxygen species, lipoxygenase, myeloperoxidase and peroxynitrite. This review is concerned with the mechanisms by which cells enhance the oxidation of LDL in the presence of transition metals; in particular, the regulation, pro- and anti-oxidant consequences, and mechanism of action of cellular thiol production are examined, and contrasted with thiol-independent oxidation of LDL in the presence of transition metals.     

脂蛋白酯酶在动脉粥样硬化发生发展中的作用

脂蛋白酯酶(lipoprotein lipase, LPL)是调节甘油三酯代谢的关键酶,在动脉粥样硬化(atherosclerosis,As)的发生发展中起重要作用。LPL产生部位的差异决定了其具有促As作用还是抗As作用。其次,不同因素对LPL的调控也会使LPL对As产生相反的作用效果。本文综述了LPL在As发生发展中的作用机制以及不同因素对LPL的调控机制,对于As的防治具有重要意义。     

基于高密度脂蛋白代谢与重塑的抗动脉粥样硬化研究及相关药物

动脉粥样硬化（atherosclerosis,AS）是一种主要因血脂代谢紊乱引发的慢性炎症性血管疾病,以血管内膜下巨噬细胞和血管平滑肌细胞过度蓄脂泡沫化为主要病理特征。高密度脂蛋白（high-density lipoprotein,HDL）通过胆固醇逆向转运（reverse cholesterol transport,RCT）将外周细胞中的胆固醇运输到肝脏然后经胆汁排出体外,从而改善血脂水平和细胞的过度蓄脂,被认为是HDL抗AS的基础。然而,大量流行病学证据表明,虽然血浆高密度脂蛋白胆固醇（high-density lipoprotein cholesterol,HDL-C）水平与心血管风险呈负相关,但仅仅提高HDL-C水平的治疗策略不一定能增加临床效益。因此,学术界认识到HDL水平不足以反映其RCT能力,而更多取决于HDL功能。本文综述了参与调节HDL功能的各种分子对HDL代谢与重塑过程的影响,以及针对上述过程的相关药物研究进展,为更全面评价HDL的抗AS作用提供理论参考。     

Low density lipoprotein (LDL), atherosclerosis and antioxidants

A crucial and causative role in the pathogenesis of atherosclerosis is believed to be the oxidative modification of low density lipoprotein (LDL). The oxidation of LDL involves released free radical driven lipid peroxidation. Several lines of evidence support the role of oxidized LDL in atherogenesis. Epidemiologic studies have demonstrated an association between an increased intake of dietary antioxidant vitamins, such as vitamin E and vitamin C and reduced morbidity and mortality from coronary artery diseases. It is thus hypothesized that dietary antioxidants may help prevent the development and progression of atherosclerosis. The oxidation of LDL has been shown to be reduced by antioxidants, and, in animal models, improved antioxidants may offer possibilities for the prevention of atherosclerosis. The results of several on going long randomized intervention trials will provide valuahle information on the efficacy and safety of improved antioxidants in the prevention of atherosclerosis. This review a evaluates current literature involving antioxidants and vascular disease, with a particular focus on the potential mechanisms.     

Relationship between low-density lipoprotein subclasses and asymptomatic atherosclerosis in subjects from the atherosclerosis risk in communities (ARIC) Study

Low-density lipoprotein (LDL) particle size has been associated with coronary heart disease, but an association between LDL size and preclinical atherosclerosis is less well established. Using gradient gel electrophoresis, large (A), intermediate (I) and small (B) LDL size subclasses were determined in 198 cases with asymptomatic carotid artery atherosclerosis (determined by B-mode ultrasonography) and 318 controls from the Atherosclerosis Risk in Communities (ARIC) Study. In Caucasians, a smaller LDL size was more prevalent in men and associated with a higher body mass index, hypertension prevalence, and plasma total- and LDL-cholesterol and triglycerides, but lower HDL-cholesterol. In African-Americans, a smaller LDL size was associated with higher triglycerides and lower HDL-cholesterol and hypertension prevalence. In Caucasians, Subclass B prevalence was 29.1% among cases and 14.8% among controls. The odds ratio (95% confidence interval) for Subclass B rather than Subclass A in Caucasian cases was 2.94 (1.67-5.17); the association remained significant after controlling for age, body mass index, smoking, and either plasma triglycerides or HDL-cholesterol. In African-Americans, however, there was no significant association between LDL subclass and case status. A predominance of smaller LDL particles is associated with asymptomatic carotid artery atherosclerosis in Caucasians, through mechanisms that remain to be elucidated.     

Relationship between low-density lipoprotein subclasses and asymptomatic atherosclerosis in subjects from the atherosclerosis risk in communities (ARIC) Study

Low-density lipoprotein (LDL) particle size has been associated with coronary heart disease, but an association between LDL size and preclinical atherosclerosis is less well established. Using gradient gel electrophoresis, large (A), intermediate (I) and small (B) LDL size subclasses were determined in 198 cases with asymptomatic carotid artery atherosclerosis (determined by B-mode ultrasonography) and 318 controls from the Atherosclerosis Risk in Communities (ARIC) Study. In Caucasians, a smaller LDL size was more prevalent in men and associated with a higher body mass index, hypertension prevalence, and plasma total- and LDL-cholesterol and triglycerides, but lower HDL-cholesterol. In African-Americans, a smaller LDL size was associated with higher triglycerides and lower HDL-cholesterol and hypertension prevalence. In Caucasians, Subclass B prevalence was 29.1% among cases and 14.8% among controls. The odds ratio (95% confidence interval) for Subclass B rather than Subclass A in Caucasian cases was 2.94 (1.67–5.17); the association remained significant after controlling for age, body mass index, smoking, and either plasma triglycerides or HDL-cholesterol. In African-Americans, however, there was no significant association between LDL subclass and case status. A predominance of smaller LDL particles is associated with asymptomatic carotid artery atherosclerosis in Caucasians, through mechanisms that remain to be elucidated.     

Oxidized LDL autoantibodies are related to apolipoprotein E phenotype,independently of postprandial change in plasma triglycerides and LDL size,among patients with angiographically verified coronary artery disease and healthy controls

OBJECTIVE: Oxidized low-density lipoprotein (LDL) autoantibodies (oxLDLab), apolipoprotein E (apoE) phenotype, postprandial triglyceride changes and LDL size are suggested to be risk factors for coronary artery disease (CAD). Our aim was to study the interaction between these new risk factors among patients with CAD and healthy controls. METHODS: oxLDLab from 31 men with angiographically verified CAD and 31 healthy men were analyzed by enzyme-linked immunosorbent assay. Isoelectric focusing and immunoblotting were used for apoE phenotyping. Triglyceride level was measured after 12 h of fasting and 3, 5 and 7 h after a high-fat meal. Nondenaturing gradient gel electrophoresis was used to separate LDL particles according to size. RESULTS: oxLD- Lab levels increased according to apoE phenotype in the following order: E2 < E3 < E4 (p = 0.004, ANOVA). The postprandial response of triglycerides, the size of LDL particles and the concentration of LDL and high-density lipoprotein (HDL) cholesterol did not differ between apoE phenotypes, and the use of these variables as covariates did not change the statistically significant difference in oxLDLab levels between apoE phenotypes (p = 0.01, ANCOVA). oxLDLab levels did not differ between the patient and control groups. CONCLUSION: We found an association between apoE allele epsilon2 and decreased levels of oxLDLab, which was independent of the postprandial response of triglycerides, the size of LDL particles and plasma LDL and HDL cholesterol levels. The mechanism by which apoE affects oxidation of LDL remains unknown.     

High-density lipoprotein functionality and breast cancer: A potential therapeutic target

Breast cancer is a major cause of death globally, and particularly in developed countries. Breast cancer is influenced by cholesterol membrane content, by affecting the signaling pathways modulating cell growth, adherence, and migration. Furthermore, steroid hormones are derived from cholesterol and these play a key role in the pathogenesis of breast cancer. Although most findings have reported an inverse association between serum high-density lipoprotein (HDL)-cholesterol level and the risk of breast cancer, there have been some reports of the opposite, and the association therefore remains unclear. HDL is principally known for participating in reverse cholesterol transport and has an inverse relationship with the cardiovascular risk. HDL is heterogeneous, with particles varying in composition, size, and structure, which can be altered under different circumstances, such as inflammation, aging, and certain diseases. It has also been proposed that HDL functionality might have a bearing on the breast cancer. Owing to the potential role of cholesterol in cancer, its reduction using statins, and particularly as an adjuvant during chemotherapy may be useful in the anticancer treatment, and may also be related to the decline in cancer mortality. Reconstituted HDLs have the ability to release chemotherapeutic drugs inside the cell. As a consequence, this may be a novel way to improve therapeutic targeting for the breast cancer on the basis of detrimental impacts of oxidized HDL on cancer development.     

长链非编码RNA(lncRNA)在氧化型低密度脂蛋白诱导血管内皮细胞损伤中表达谱的变化

目的:探讨长链非编码RNA(long noncoding RNA,lnc RNA)在氧化型低密度脂蛋白(oxidized low-density lipoprotein,ox-LDL)诱导的损伤人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVEC)与正常HUVEC中表达谱的差异。方法:采用lnc RNA芯片检测ox-LDL诱导的损伤HUVEC与正常HUVEC中lncRNA及mRNA的表达差异,筛选出HUVEC损伤相关的lncRNA。结果:相对于正常HUVEC,在ox-LDL诱导的损伤HUVEC中表达上调和下调超过2倍的lncRNAs和m RNAs分别有139种和113种,上调和下调超过4倍的lncRNAs和mRNAs分别有35种和28种。结论:与正常HUVEC比较,ox-LDL诱导的损伤HUVEC中lncRNA的表达谱显著变化,lncRNA可能在血管内皮细胞损伤过程中发挥一定作用。     

氧化修饰低密度脂蛋白与动脉粥样硬化

动脉粥样硬化的发生发展与低密度脂蛋白受到氧化修饰有关。本文从以下四个方面对本室的工作进行了综述：（１）动脉粥样硬化机体受到脂质过氧化损伤;（２）Ｏｘ－ＬＤＬ对内皮细胞、平滑肌细胞和巨噬细胞的毒性效应;（３）Ｏｘ－ＬＤＬ和ＭＤＡ－ＬＤＬ的比较及与Ｏｘ－ＬＤＬ和ＭＤＡ－ＬＤＬ结合的清道夫受体的特征;（４）不同方法对ＬＤＬ氧化修饰的比较和以ＬＤＬ氧化修饰为模型对某些物质的抗氧化修饰研究。研究结果为动脉粥     

Dissociation of apoptosis induction and CD36 upregulation by enzymatically modified low-density lipoprotein in monocytic cells.

Modified low-density lipoprotein (LDL) has been implicated as an initiating or amplifying factor in atherogenesis. Some of its biological activities, such as apoptosis induction and upregulation of the scavenger receptor CD36, appear to share common signaling pathways in cells of the cardiovascular system. Exposure of low-differentiated monocytic cells to LDL modified with 15-lipoxygenase and secretory phospholipase A(2) induced apoptosis and upregulated CD36. Cell treatment with constituents of modified LDL, such as 13-hydroxyoctadecadienoic acid (13-HODE), 25-hydroxycholesterol, and lysophosphatidyl choline, and with an unrelated apoptogen (TNF-related apoptosis-inducing ligand) induced apoptosis. In contrast, only 13-HODE caused upregulation of CD36 expression. Cotreatment with the pan-caspase inhibitor z.VAD-fmk resulted in suppression of apoptosis, but was without any effect on CD36 expression. These data indicate that in monocytic cells enzymatically modified LDL is capable of inducing both apoptosis and upregulation of CD36 expression. However, in our cellular model, the two induction processes appear to be causally unrelated.     

Oxidized Low-Density Lipoprotein Induces Neuronal Death

Low-density lipoprotein (LDL) exists within the brain and is highly vulnerable to oxidative modifications. Once formed, oxidized LDL (oxLDL) is capable of eliciting cytotoxicity, differentiation, and inflammation in nonneuronal cells. Although oxLDL has been studied primarily for its role in the development of atherosclerosis, recent studies have identified a possible role for it in neurological disorders associated with oxidative stress. In the present study application of oxLDL, but not LDL, resulted in a dose- and time-dependent death of cultured rat embryonic neurons. Studies using pharmacological inhibitors implicate the involvement of calcium, reactive oxygen species, and caspases in oxLDL-induced neuronal death. Coapplication of oxLDL with either amyloid beta-peptide or glutamate, agents that enhance oxidative stress, resulted in increased neuronal death. Taken together, these data demonstrate that oxLDL induces neuronal death and implicate a possible role for oxLDL in conditions associated with increased levels of reactive oxygen species, including Alzheimer's disease.     

In vitro interactions of phenformin with serum lipoproteins and consequences thereof.

Turbidity developed when phenformin was added to human serum; this turbidity increased in a sigmoidal fashion with rising concentrations of phenformin (5–50 nmole/1). Centrifugation produced clearing of the solution, with collection of particulate matter on the surface of the sera.Extraction of control, and phenformin-treated sera with petroleum ether for 15 min. revealed that cholesterol and triglyceride were responsible for the turbidity. Different sera produced different turbidities with a given concentration of phenformin. No significant simple correlation existed between turbidity and serum cholesterol and/or triglyceride levels. The turbidities, produced by the addition of a constant concentration of phenformin to a series of diluted serum samples, were linearly related to the amount of serum present.The turbidities acquired by purified very-low density (VLDL), low-density (LDL), and high-density lipoprotein (HDL) fractions with phenformin were additive, and the turbidity of phenformin-treated serum was accounted for by these lipoprotein fractions. Serum free of lipoproteins did not become turbid when exposed to phenformin. Phenformin added to serum which had previously been delipidated, failed to produce turbidity. The turbidity produced by phenformin was reversible, because it could easily be cleared by dialysis.No significant differences in quantitative immunochemical reactivities were observed when control serum was compared with the subnatant of phenformin-treated serum, as determined by single radial immunodiffusion with LDL antibodies.These in vitro observations may be related to the in vivo hypolipidemic action of phenformin on hyperlipidemic subjects.     

氧化磷脂与动脉粥样硬化

磷脂是构成生物膜和脂蛋白的重要成分,容易在自由基或非自由基以及酶促条件下发生氧化修饰,形成氧化磷脂(oxidized phospholipids,OxPLs),并进一步产生具有不同生物活性的氧化产物.临床证据表明,OxPLs在动脉粥样硬化(ath-erosclerosis,AS)发展过程中不断生成和转化,并在病变处积累...     

Genetic analysis of murine strains C57BL/6J and C3H/HeJ to confirm the map position ofAth-1, a gene determining atherosclerosis susceptibility

Previous results suggested that strains C57BL/6J and C3H/HeJ differed in a single gene for atherosclerosis susceptibility, calledAth-1. Based on data from recombinant inbred strainsAth-1 was tentatively assigned to chromosome 1 linked toAlp-2. In this report, a cross between C57BL/6 and C3H/HeJ was carried out in order to test whether the tentative map position was correct. Parental strains and F₁ and F₂ progeny were examined. Susceptible alleles ofAth-1, found in C57BL/6, are associated with relatively low levels of high-density lipoprotein (HDL)-cholesterol in animals fed an atherogenic diet; resistant alleles ofAth-1 are associated with relatively high levels of HDL-cholesterol. F₁ progeny have HDL levels that are intermediate between these of the two parental strains. Among the F₂ progeny,Alp-2 andAth-1 cosegregated, providing confirmatory evidence thatAth-1 is linked toAlp-2 on chromosome 1. Three mice recombinant forAlp-2 andAth-1 were found among the 60 chromosomes tested, giving an estimated map distance between these two genes of 5.0±2.8 (SE) cM. The phenotypic characteristics ofAth-1 resemble a genetic trait in humans, hyperalphalipoproteinemia, which is characterized by elevated levels of HDL-cholesterol, reduced risk of heart disease, and increased longevity.This work was supported by Grant HL-32087 from the Heart, Lung, and Blood Institute, National Institutes of Health, Grant 1858 from the Council for Tobacco Research, Grant 86-1387 from the American Heart Association with funds contributed in part by the Alameda, Orange, and Santa Barbara County Chapters, and Grants 85-N132A and 85-N136A from the California Affiliate of the American Heart Association.