低密度脂蛋白测定方法的选择

聚乙烯硫酸(PVS)沉淀法测定181例标本的低密度脂蛋白胆固醇(LDL-C)值,并与Friedwald公式的计算结果比较,按三酰甘油(TG)浓度分组,对比两法LDL-C的差异及影响LDL-C值的因素。结果显示,在低浓度TG时两法基本一致,高TG两法差别较大,TG>4.52mmol/L时Friedwald公式计算结果偏低。     

低密度脂蛋白血液净化研究进展

冠心病与低密度脂蛋白(IDL)浓度过高有着密切关系，低密度脂蛋白血液净化已成为一种有效的治疗严重高胆固醇血症方法被广泛采用的。文章综述了低密度脂蛋白血液净化的方法及其净化材料研究概况。     

低密度脂蛋白作为药物载体的研究进展

对近年来低密度脂蛋白作为新型药物载体靶向药物剂型的理论基础及实际应用研究进行了综述     

低密度脂蛋白受体研究进展

本文介绍了低密度脂蛋白受体蛋白的分子结构、基因特征和基因突变的种类，从基因治疗、抗肿瘤、抗病毒和药物筛选等几个方面阐述了低密度脂蛋白受体在医药方面的应用及一些新进展。并对低密度脂蛋白受体的基因工程表达情况和低密度脂蛋白与动脉粥样硬化的关系作了阐述。对低密度脂蛋白受体进行深入研究将会有助于对心血管疾病发病机理的进一步理解，同时对抗心血管疾病药物的开发有可能产生积极的作用。     

氧化修饰低密度脂蛋白与冠心病相关性研究

探讨冠心病（ＣＨＤ）患者因中氧化修饰氏密度脂蛋白（ＯＸＬＤＬ）的含量变化和异常检出率与其与冠状动脉造影的相关性。     

低密度脂蛋白作为药物靶向载体的研究进展

低密度脂蛋白作为一种内源性纳米颗粒,具有良好的生物相容性、可彻底生物降解、无免疫原性,不被体内网状内皮系统识别而快速清除,是一种值得研究的药物主动靶向载体。此文主要介绍了近年来低密度脂蛋白作为肿瘤诊断与治疗靶向载体的研究新进展。     

维拉帕米增强猴肾上皮细胞低密度脂蛋白受体活性

本文用放射配体法观察了维拉帕米对恒河猴肾上皮细胞ＬＤＬ受体活性的影响，发现Ｖｅｒ以浓度和时间依赖的方式明显增强受体介导的结合和内移过程，对降解的影响不显著，Ｖｅｒ作用深度为４４ｍｍｏｌ．Ｌ＾－１效应最明显。     

番茄红素对低密度脂蛋白氧化的影响

目的研究番茄红素对低密度脂蛋白氧化的影响,探讨其抗动脉粥样硬化作用机制。方法密度梯度超速离心法分离人血浆LDL,观察番茄红素对铜离子诱导的LDL氧化的影响;通过喂饲高脂饲料建立家兔高脂血症模型,观察番茄红素对LDL氧化易感性及血清氧化低密度脂蛋白水平的影响。结果番茄红素能明显抑制铜离子诱导的LDL氧化,降低高脂血症家兔LDL氧化易感性和血清Ox-LDL水平。结论番茄红素在体内外均能明显抑制LDL氧化修饰,这可能是其抗AS主要机制之一。     

冠心病患者氧化低密度脂蛋白自身抗体的变化

目的 探讨血清氧化低密度脂蛋白自身抗体(Ab-ox-LDL)与冠心病患者病变稳定性及病变程度的关系.方法 根据临床诊断标准和冠状动脉造影结果 ,将60例患者分为非冠心病(CON)组、不稳定型心绞痛(UAP)组和稳定型心绞痛(SAP)组,采用ELISA法测定血清Ab-ox-LDL浓度.结果 UAP组血清Ab-ox-LDL水平明显高于SAP和CON组(P＜0.05),SAP组高于CON组(P＜0.05);Ab-ox-LDL在UAP组和SAP组呈高度正相关(P＜0.05).结论 血清Ab-ox-LDL与冠心病患者病变的严重程度和冠心病斑块的稳定性密切相关,在冠状动脉硬化进程中可能起着重要的作用.     

小而密低密度脂蛋白的研究进展

血浆低密度脂蛋白 (lipoproteinLDL)具有异质性 ,由一系列大小、密度和化学组成各异的颗粒组成。血浆甘油三酯水平越高 ,生成的小而密LDL越多。近年来对LDL亚组份与冠心病的关系进行了深入的研究 ,认为小而密LDL在动脉粥样硬化的发生中起重要作用 ,是冠心病的危险因子。小而密LDL亚组分比密度较低的较大颗粒更具有致动脉硬化性 ,可能与其更易被氧化、诱导内皮细胞表达粘附因子有关。     

Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake

We highlight the importance of the low-density lipoprotein (LDL) receptor family and its pharmaceutical implications in the field of drug delivery. The members of the LDL receptor family are a group of cell surface receptors that transport a number of macromolecules into cells through a process called receptor-mediated endocytosis. This process involves the receptor recognizing a ligand from the extracellular membrane (ECM), internalizing it through clathrin-coated pits and degrading it upon fusion with lysosomes. There are nine members of the receptor family, which include the LDL receptor, low-density lipoprotein-related protein (LRP), megalin, very low-density lipoprotein (VLDL) receptor, apoER2 and sorLA/LRP11, LRP1b, MEGF7, LRP5/6; the former six having been identified in humans. Each member is expressed in a number of different tissues and has a wide range of different ligands, not specific to the recognition of the LDL particle. Thus, rather than the original hypothesis that the receptor is only a mediator of cholesterol uptake, it may also be involved in a number of other physiological functions, including the progression of certain disease states and, potentially, cellular drug uptake. A number of studies have suggested that the LDL receptors are involved in endocytosis of drugs and drug formulations including aminoglycosides, anionic liposomes and cyclosporine A (CsA). This article reviews the importance of lipoproteins as a drug delivery system and how LDL receptors are relevant to the design and targeting of specific drugs.     

Probucol reduces lysophosphatidylcholines in low-density lipoprotein

OBJECTIVES: Lysophosphatidylcholine (LPC) in low-density lipoprotein (LDL) comes into notice as an important atherogenic substance. METHODS: Since the effect of probucol, an antioxidative lipid-lowering drug, on LPC molecular species has not been elucidated, two LPC molecular species, stearoyl LPC (SLPC) and palmitoyl LPC (PLPC), were measured in LDL using high-pressure liquid chromatography. LDL was obtained from 11 hyperlipidemic patients, including 9 diabetic patients, in comparison with 11 age- and gender-matched controls. RESULTS AND CONCLUSION: Hyperlipidemic patients showed nearly twofold higher levels of SLPC and PLPC per gram of LDL protein than those of controls. All hyperlipidemic patients were treated with oral administration of 500 mg/day of probucol for 3 months. Both LPCs in LDL were significantly reduced to control levels and were increased again up to the pretreatment levels 4 weeks after cessation of the treatment. Therefore, probucol has a potent effect in reducing LPC and may contribute to decreasing the atherogenicity of LDL.     

The low-density lipoprotein cholesterol-lowering effect of pravastatin and factors associated with achieving targeted low-density lipoprotein levels in an African-American population

STUDY OBJECTIVES: To describe the low-density lipoprotein cholesterol (LDL)-lowering effect of pravastatin in African-American patients and to identify factors associated with achieving National Cholesterol Education Program (NCEP)-defined target levels. DESIGN: Retrospectively defined cohort study. SETTING: Large, government-owned, teaching hospital. PATIENTS: Eighty-four African-American patients starting therapy with pravastatin in October-November 1997. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Whether or not target LDL concentrations were achieved was used to measure efficacy. Stepwise logistic regression identified the target LDL, baseline LDL, and baseline high-density lipoprotein cholesterol (HDL) as significant predictors of achieving the target. The proportion of patients achieving their target LDL when that target was below 160, below 130, and 100 mg/dl or below was 64%, 32%, and 13% (p=0.004), respectively. Medical record review identified the reasons for not achieving target as incorrect drug regimen, inadequate lipid monitoring, and noncompliance. CONCLUSION: These results indicate that substantial numbers of patients receiving lipid-lowering therapy are not meeting NCEP-defined targets and that with increased drug monitoring and compliance, improvements in achieving NCEP target LDL levels could be realized.     

Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein

Troglitazone (T) is a member of a new class of antidiabetic drugs termed thiazolidinediones (TZDs), which has previously been used as an anti-diabetic agent. In this study we investigated the influence of T, a ligand for PPAR-gamma receptor, on copper-catalyzed or cell-mediated oxidation of native, glycated, and glycoxidated low-density lipoprotein (LDL). A dose-dependent inhibition of copper-mediated low-density lipoprotein-oxidation, as monitored by the formation of oxidation-specific fluorescence, was observed for both native and glycated low-density lipoprotein. At the concentration of 20 microg/mL the inhibition amounted from 14.7% to 64.7% by all low-density lipoprotein forms. For glycated low-density lipoprotein we obtained the highest oxidation rate, but the most pronounced inhibition by T was found for glycoxidated low-density lipoprotein (goLDL). Inhibitory effects of T were also investigated by measurement of relative electrophoretic mobility (REM) in the concentration range of 0 to 20 microg/mL. The inhibition of 4h oxidation of native low-density lipoprotein was found in the entire concentration range, but significance was seen at 10 microg/mL. The long-term glycation and glycoxidation of low-density lipoprotein as measured by 5-hydroxymethyl-2-furaldehyde (5-HMF) formation and binding of fructosamine was found to be inhibited by T. In endothelial cell-mediated oxidation of low-density lipoprotein cytotoxicity of T in the concentration range of 0 to 160 microg/mL during 2 to 24 h oxidation was investigated. In the non-cytotoxic concentration range of 5 to 20 microg/mL, a significantly reduced liberation of isoprostane 8-epi-PGF2alpha during 24 h cell-mediated oxidation of low-density lipoprotein and its modifications was found. This inhibitory action of T was most significant in the case of goLDL and amounted to approximately 20% to 60% inhibition at 5 to 20 microg/mL T, respectively. In the concentration range of 40 to 160 microg/mL, however, T showed an increasing cytotoxic action, as evidenced by loss of cell adhesion, loss of cellular protein, morphological changes, and cell disintegration as well as by strongly enhanced troglitazone-mediated isoprostane 8-IP liberation (fivefold to sixfold). T may be used as a model to explore the thiazolidinediones' mechanism on oxidation in a more general aspect for treatment for T2DM, because T is not clinically available.     

Perspectives on low-density lipoprotein cholesterol goal achievement

ABSTRACT

Background: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of coronary heart disease (CHD). European and US guidelines now recommend lower LDL-C levels, particularly in high-risk patients. Although LDL-C treatment goals to reduce the risk of CHD are clear, many patients do not reach their LDL-C goals.

Objectives: Examine consensus guideline targets for LDL-C lowering in patients at high or very high cardiovascular risk; examine cholesterol goal achievement in clinical practice; evaluate the effectiveness of ezetimibe/statin and other adjunctive lipid-lowering treatments in achieving LDL-C goals; and consider ongoing controversies and the randomized controlled trials that may help to resolve or better illuminate them.

Methods: An English-language PubMed search was conducted to identify prospective randomized controlled trials, open-label studies, and retrospective and observational studies from 2001 (same year that the executive summary of the National Cholesterol Education Program's Adult Treatment Panel III was published) to present for an analysis of the effects of adjunctive therapies on LDL-C lowering and goal attainment in patients at elevated cardiovascular risk.

Results: Elevated LDL-C is the primary target of lipid-lowering therapy; aggressive lowering is of great benefit to those at high risk. Statins are recommended first-line lipid-lowering agents, with a long, well-regarded history of efficacy and safety. Not all patients, however, can achieve recommended LDL-C goals simply using starting doses of statins. For such patients, more intensive therapy utilizing high-dose statins or combination therapy, including statins combined with other lipid-lowering agents, such as ezetimibe, bile acid resins (BARs), or niacin, is warranted. Potential limitations of the present review include possible publication bias and the focus on pharmacotherapy rather than lifestyle modification and the important objective of multiple risk-factor modification to reduce absolute global cardiovascular risk.

Conclusions: With a well-established link between elevated LDL-C and cardiovascular risk, aggressive LDL-C lowering becomes particularly important. Patients needing intensive LDL-C lowering to achieve goals will often require adjunctive treatments, including ezetimibe, BARs, or niacin along with statins. Given both their high mg: mg potency in lowering LDL-C and favorable tolerability and patient acceptance/adherence profile, ezetimibe/statin combination regimens arguably provide the greatest likelihood for patients to reach new, lower LDL-C targets; however, efficacy and safety data of any adjunctive treatment, along with drug costs and patient adherence to treatment (partly related to complexity of the regimen) all need to be considered when determining the optimal regimen to achieve LDL-C goals in individual patients according to their baseline absolute cardiovascular risk, LDL-C level, and consensus LDL-C targets.     

氧化低密度脂蛋白对细胞滋养细胞浸润能力的影响

目的:探讨不同浓度氧化低密度脂蛋白(oxLDL)对细胞滋养细胞浸润能力的影响.方法:采用蛋白印迹法和RT-PCR技术检测不同浓度oxLDL(0.01,0.02,0.05,0.1 mg/mL)刺激下细胞滋养细胞中过氧化物酶体增殖物激活受体γ(PPARγ)蛋白及其mR-NA的表达:并检测相应浓度oxLDL对细胞滋养细胞能力的影响.结果:(1)不同浓度oxLDL(0.01,0.02,0.05,0.1mg/mL)刺激下细胞滋养细胞中PPAR-γ蛋白表达水平(15.0±2.0,18.4±2.8,21.3±2.4,25.8±3.0)与对照组(13.3±2.2)比较差异有统计学意义(P<0.01),各组分别比较差异亦有统计学意义P<0.01;(2)不同浓度oxLDL(0.01,0.02,0.05,0.1 mg/mL)刺激下细胞滋养细胞PPARγmRNA表达水平(14.9±3.1,17.2±4.0,19.4±3.2,21.7±3.0)与对照组(12.1±3.3)比较差异有统计学意义P<0.01,各组分别比较差异亦有统计学意义P<0.01;(3)不同浓度oxLDL(0.01,0.02,0.05,0.1mg/mL)刺激下细胞滋养细胞浸润指数(0.66±0.04,0.58±0.03,0.46±0.04,0.32±0.05),与对照组(0.69±0.05)比较差异有统计学意义P<0.01,各组分别比较差异亦有统计学意义P<0.01;(4)oxLDL浓度与细胞滋养细胞的浸润指数呈负相关,(r=-0.98,P<0.01);与细胞滋养细胞PPARγmRNA表达水平呈正相关(r=0.93,P<0.01).结论:oxLDL浓度升高可上调细胞滋养细胞中PPARγ的表达,从而影响细胞滋养细胞的浸润能力.     

Biological activity of Asp-hemolysin as a regulation factor to atherogenic effect by oxidized low-density lipoprotein

Oxidatively modified low-density lipoprotein (OxLDL) is present in atherosclerotic lesions and has been proposed to play an important role in atherogenesis. Asp-hemolysin, a hemolytic toxin from Aspergillus fumigatus, is a binding protein for OxLDL. This study was undertaken to clarify the biological activity of OxLDL and the potentially of Asp-hemolysin as a regulation factor to atherogenic effect by OxLDL. We first analyzed the interaction between OxLDL and blood coagulation factors, which are involved in the blood coagulation pathway. OxLDL caused prolongation of activated partial thromboplastin time (APTT) as a parameter of the intrinsic pathway of blood coagulation in a dose- and oxidation time-dependent manner. In addition, OxLDL significantly inhibited blood coagulation factor VIII, IX, and XI activity. Furthermore, we demonstrated that factor VIII binds to OxLDL. These results indicate that the binding of factor VIII to OxLDL affects the intrinsic pathway of the blood coagulation cascade. Next, to clarify the structure-function relationship of Asp-hemolysin, we expressed Asp-hemolysin in Escherichia coli as a fusion protein with a maltose-binding protein (MBP) and purified it by affinity chromatography. The purified recombinant Asp-hemolysin showed an immunoreactivity with the anti-Asp-hemolysin antibody. In addition, MBP-Asp-hemolysin fusion protein exhibited binding activity to Ox-LDL as did native Asp-hemolysin. Furthermore, to investigate the effect of the Asp-hemolysin-related peptide (P-21), a synthetic peptide derived from a region of Asp-hemolysin that is rich in positive charges, on macrophage proliferation induced by OxLDL. P-21 inhibited OxLDL-induced macrophage proliferation in a dose-dependent manner. In addition, the binding analysis of P-21 to OxLDL indicated that P-21 binds to OxLDL. These results indicate that P-21 inhibits the OxLDL-induced macrophage proliferation through binding of P-21 to OxLDL. In conclusion, we have shown that OxLDL affects the intrinsic pathway of blood coagulation, and its mechanism is dependent on the binding of factor VIII to OxLDL. Furthermore, we indicate the possibility that Asp-hemolysin is a useful tool to investigate the pathophysiological significance of OxLDL. In particular, since the P-21, an Asp-hemolysin-related peptide, inhibits the OxLDL-induced macrophage proliferation through binding of P-21 to OxLDL, further study on the binding mechanism between Asp-hemolysin-related peptide and OxLDL may provide important information on the prevention and treatment of atherosclerosis.