脂蛋白α与动脉粥样硬化

脂蛋白a（Lipoprotein（a），Lp（a））是与低密度脂蛋白（low density lipoprotein，LDL）相似的一种脂蛋白，有足够证据表明，Lp（a）是动脉粥样硬化性疾病的一项独立危险因子，本文就Lp（a）的生物化学特性、代谢、可能的致动脉粥样硬化机制及与冠心病关系作一综述。     

脂蛋白（a）及低密度脂蛋白与成纤维细胞表面结合特性的比较

脂蛋白（a)[Lipoprotein(a),Lp(a)]的代谢途径尚有争议。本文比较研究了Lp(a)和低密度脂蛋白（Low Density Lipoprotein,LDL)与成纤维细胞表面的结合特性，结果显示，Lp(a)与成纤维细胞呈特异性，高亲和力，可饱和性结合，但是Lp(a)与细胞的亲和力，最大结合容量均比LDL低，竞争性结合试验显示LDL只能部分抑制Lp(a)与成纤维细胞表面特异性的结合；细胞表面LDL受体活性的下调，可使LDL与细胞的结合量下降58％，而Lp(a)的结合量仅下降12．3％，这些结果表明LDL受体只能参与部分Lp(a)与细胞表面的结合及代谢。     

载脂蛋白(a)基因结构与功能研究

脂蛋白(a)[Lp(a)]是一种低密度脂蛋白(LDL)样的脂蛋白。LDL样脂蛋白是致动脉粥样硬化的主要危险因素。LDL样脂蛋白与Lp(a)不同之处就在于前者比后者多个载脂蛋白(a)[apo(a)]。apo(a)基因结构与血纤维蛋白溶酶原同源。apo(a)与血纤维蛋白溶酶原活性竞争可以说明一些与Lp(a)有关的病理生理学问题。现已识别6个高度相关的基因,至少在重叠的基因组克隆附近发现4个相关基因。目前正着于研究apo(a)基因表达的调节,人类apo(a)基因插入到转基因鼠,此基因导致了转基因鼠动脉损害。     

氧化修饰低密度脂蛋白、生长因子、细胞因子与动脉粥样硬化

<正>近年认为,动脉粥样硬化（AS）是由于动脉壁的内皮细胞和血管平滑肌细胞（VSMC）受多种危险因子的损伤而使机体产生的一种过度的炎症增生性反应过程,其中大量的生长因子、细胞因子和血管调节因子参与了此反应过程。低密度脂蛋白（LDL）发生氧化修饰形成氧化修饰低密度脂蛋白（OX-LDL）是AS发生发展的关键步骤,它可以通过调节多种细胞产生分泌多种细胞因子、生长因子发挥其致AS效应。本文就OX-LDL对AS发生发展关系较为密切的几种细胞因子、生长因子的影响加以阐述。     

糖尿病合并动脉粥样硬化患者糖化血红蛋白及血糖、血脂水平分析

目的:观察糖尿病合并动脉粥样硬化(DM+AS)患者糖化血红蛋白(HbAlc)及血糖、血脂水平的变化。方法:测定32例DM+AS患者、36例单纯糖尿病(DM)患者和55例健康对照者HbAlc、空腹血糖(FBG)和血脂指标,并进行对比分析。结果:DM+AS组与单纯DM组之间FBG水平无显著性差异,HbAlc水平有显著性差异(P<0.05),且两组两指标均较正常对照组显著增高(P<0.01);总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)和脂蛋白(a)[Lp(a)]水平DM+AS组比正常对照组显著增高(P<0.01)。结论:DM+AS患者血脂水平明显升高;HbAlc作为反映血糖控制好坏的有效指标,对DM合并AS及血管病变的监测有重要作用。     

冠心病患者血清脂蛋白a、同型半胱氨酸及低密度脂蛋白水平与不良心脑血管事件的相关性分析

目的探究冠心病患者血清脂蛋白a[Lp(a)]、同型半胱氨酸(Hcy)及低密度脂蛋白(LDL)水平与不良心脑血管事件的相关性。方法回顾性分析2017年1月至2018年6月期间到我院就诊149例冠心病患者相关资料,分析随访期间患者不良心脑血管事件发生情况,依据随访期间是否出现不良心脑血管事件分为研究组与对照组,比较两组患者Lp(a)、Hcy以及LDL水平,三指标水平对不良心脑血管事件诊断价值,对三指标之间相关性进行分析。结果随访期间患者不良心脑血管事件发生率为10.07%(15/149);研究组患者血清中Lp(a)、Hcy以及LDL水平显著高于对照组(P<0.05);ROC曲线显示Lp(a)、Hcy以及LDL对不良心脑血管事件诊断最佳截断值分别为180mg/L、15μmol/L以及3.78mmoL/L,,其诊断灵敏度分别为73.27%、84.35%与81.29%,其诊断特异性分别为79.35%、81.34%以及80.24%;Pearson相关性分析显示Lp(a)与Hcy之间关系为正相关(r=0.371,P<0.05),Hcy与LDL之间为负相关(r=-0.513,P<0.05),Lp(a)与LDL之间没有相关性(r=0.068,P>0.05)。结论冠心病患者血清中Lp(a)、Hcy以及LDL水平异常升高状态会增加患者不良心脑血管事件发生风险。     

高密度脂蛋白氧化修饰与动脉硬化

大量流行病学研究证实 ,血清高密度脂蛋白(highdensitylipoprotein ,HDL)水平与动脉粥样硬化(atherosclerosis ,AS)性心脑血管疾病的发病率呈负相关 ,HDL水平降低是不亚于低密度脂蛋白 (lowdensitylipoprotein ,LDL) ,甚至比LDL更显著的AS血管疾病的危险因素[1] 。动脉壁处LDL氧化是AS始动及发展的关键这一观点已得到充分肯定。近年来发现 ,在某些外在或内在的诱因下 ,作为AS保护因子的HDL也发生与LDL相似的氧化修饰 ,HDL氧化后 ,不仅理化性质发生明显变化 ,生物学功能也发生显著改变。本文就HDL氧化易感性、体内可能的氧化部…     

凝集素样氧化型低密度脂蛋白受体-1与动脉粥样硬化的研究进展

动脉粥样硬化（Artherosclerosis，AS）是以内膜粥样斑块或纤维斑块形成为病变特征的动脉疾病，主要累及大、中动脉，使其管腔狭窄和中膜弹性降低。AS可发生于心、脑、肾等重要脏器，导致血栓、栓塞及动脉瘤形成等多种严重并发症。AS的危险因素众多，包括高脂血症、高血压、吸烟、糖尿病、静态生活模式、饮食习惯、性别、年龄及遗传等因素。其中低密度脂蛋白（Low Density Lipoprotein，LDL）可能是AS最主要的危险因素，尤其是氧化修饰的LDL（Oxidatively Modified LDL，ox—LDL）可使血管内皮细胞、平滑肌细胞、单核／巨噬细胞及成纤维细胞转化为致AS的表型。     

脂质转运和脂酶水解对低密度脂蛋白的修饰作用

采用胆固醇脂转运蛋白（CETP）介导极低密度脂蛋白（VLDL）中甘油三酯（TG）与低密度脂蛋白（LDL）中胆固醇（CH）交换：再行脂蛋白脂酶（LPL）水解LDL中TG，对LDL进行修饰，引起LDL颗粒组成和大小的变化，探讨体内小而致密的LDL形成的可能途径，及易于致动脉粥样硬化（As）作用的机制。结果示CETP介导的脂质转运使LDL中TG含量增加，CH降低，颗粒直径轻微变大；再经LPL水解的共同作用，LDL中TG含量降低，颗粒变小。同时LDL中载脂蛋白B（apoB）免疫反应性也发生相应的变化，LDL中TG含量同apoB免疫反应性高度负相关。认为大而轻的A型LDL经修饰作用可转变为小而致密的B型LDL，富含TG的LDL不易于通过apoB受体途径清除，史易于氧化。     

遗传性Lp(α)变异的临床意义

由遗传决定的Lp(α)表现型是自婴儿起就存在于个体血清中的稳定特征。由于Lp(α)脂蛋白相似于低密度脂蛋白(LDL),认为其功能可与LDL相比拟。冠心病病人Lp(α+)的出现频率高于健康人。Lp(α)型对血清胆固醇和三酸甘油脂水平有轻度影响。此外,Lp(α+)和 Lp(α-)也有个体间的生化差异(如空腹胰岛素水平、胰岛素反应、游离甲状腺素因子)。LP型对脂类水平的影响似乎太小,不足以充     

Apolipoprotein E phenotype and lipoprotein(a) in familial hypercholesterolaemia implication for lipoprotein(a) metabolism

The mechanisms regulating plasma levels of lipoprotein(a) [Lp(a)] are largely unknown. A two- to three-fold increase in Lp(a) levels in patients with familial hypercholesterolaemia (FH) has implied that LDL receptor activity may be an important factor in determining plasma Lp(a) levels, as it is in determining low-density lipoprotein (LDL) cholesterol concentration. Common apolipoprotein E (apoE) variants also affect plasma LDL cholesterol levels. We therefore examined the effect of the common apoE variants on plasma Lp(a) levels in 149 patients with heterozygous FH. Patients with the apoE₂ allele (n = 11) had significantly higher plasma levels of LDL cholesterol compared to those with a apoE₃E₃ phenotype, while patients with the apoE₄ isoform had similar levels. However, there was a significant effect of the apoE₂ allele in lowering Lp(a) levels, compared to the apoE₃E₃ group. The median Lp(a) concentration in patients possessing an apoE₂ isoform was 13.1 mg/dl below the median, while in those with an apoE₄ allele the median Lp(a) levels were 4.13 mg/dl higher. There was a marked inverse correlation between plasma Lp(a) and LDL cholesterol concentration in the FH patients carrying the apoE₂ allele. Our data imply that difference in Lp(a) levels observed between FH patients with different apoE isoforms does not result from altered clearance of Lp(a) via the LDL receptor pathway, and suggest that apoE mediated hepatic up-take, or conversion, of remnant particles may be determining Lp(a) production rate.Abbreviations apo apoprotein - CHD coronary heart disease - FH familial hypercholesterolaemia - HDL high-density lipoprotein - LDL low-density lipoprotein - Lp(a) lipoprotein(a)     

Effects of menopause and hormone replacement therapy on plasma lipids, lipoproteins and LDL-receptor activity

A cross-sectional study of ninety six women was conducted to examine the effect of menopause and hormone replacement therapy (HRT) on plasma lipids, lipoproteins and oxidation of low density lipoproteins. The sample consisted of 26 premenopausal women, 26 postmenopausal women taking no replacement hormones and 43 postmenopausal women on hormone replacement therapy. Postmenopausal women not taking replacement hormones had significantly higher plasma cholesterol, low density lipoprotein (LDL) cholesterol and lipoprotein[a] (Lp[a]) levels compared to premenopausal women or postmenopausal women on HRT [6.00±0.15, 5.36±0.17 (P<0.01), 5.63±0.13 (P<0.05) mmol/l, respectively for total cholesterol; 4.13±0.15, 3.64±0.15 (P<0.05), 3.82±0.12 (P<0.05) mmol/l, respectively for LDL-cholesterol; 48.19±9.90, 26.59±5.53 (P<0.03), 25.12±4.62 (P<0.03) mg/dl, respectively for Lp[a]]. The differences in LDL cholesterol concentrations were inversely related to changes in LDL receptor activity (r=−0.27, P<0.01). HRT use was found to be associated with a significantly smaller LDL particle size. Plasma triglyceride was significantly higher in women on HRT (1.16±0.07 mmol/l) than in the premenopausal group (0.96±0.07) or postmenopausal group not using HRT (0.87±0.06). There were no differences in LDL oxidation between the groups when LDL was oxidised in the presence of copper. Nor was there any difference in the uptake of copper-oxidised or macrophage-modified LDL into J774 macrophages. These results confirm the effect of menopause and exogenous hormones on plasma lipids and lipoproteins, and suggest that HRT modifies the activity of the LDL receptor. Hormone replacement did not appear to protect LDL from oxidation.     

人主动脉粥样硬化病变中修饰脂蛋白的研究

目的研究人粥样硬化病变主动脉中丙二醛（ＭＤＡ）和４羟基壬烯醛（ＨＮＥ）修饰载脂蛋白Ｂ（ａｐｏＢ）的分布特点、含量和理化特性,并与脂蛋白（ａ）［Ｌｐ（ａ）］和ａｐｏＢ的分布进行比较。方法应用免疫组织化学、电镜、免疫电镜以及生物化学等方法进行定性或定量分析。结果ＭＤＡ和ＨＮＥ－ａｐｏＢ在细胞外基质中的分布与Ｌｐ（ａ）和ａｐｏＢ一致,但在泡沫细胞内则有不同。ＭＤＡ－ａｐｏＢ和ＨＮＥ－ａｐｏＢ在泡沫细胞内呈环状、孔状分布,与蜡样色素相似。病变动脉内膜低密度脂蛋白的超微结构、化学成分及电泳行为均与体外修饰脂蛋白相似,其醛类修饰ａｐｏＢ含量明显高于无病变者。结论脂蛋白的氧化性修饰是动脉粥样硬化发生的必要条件。     

In vitro studies of the interaction of calcium ions and other divalent cations with the Lp(a) lipoprotein and other isolated serum lipoproteins

The interaction of isolated Lp(a) lipoprotein with different divalent cations was studied and compared to that of other isolated lipoprotein classes.
Purified Lp(a) lipoprotein was found to be most sensitive to the metal ions tested, and the Lp(a) lipoprotein was the only lipoprotein which was precipitated by calcium ions alone. The precipitation apparently depends on the ionic radii of the cations used as well as on the lipoprotein class tested. The precipitation reaction between calcium ions and the Lp(a) lipoprotein, and the interaction between calcium ions and LDL (without precipitation) seem to follow the known rules for small ion - macromolecule interaction reasonably well. The calcium ion - Lp(a) lipoprotein interaction results in a small aggregate. The binding is of ionic type and the precipitation reaction is initially reversible. It was estimated that LDL particles have a mean of 290 equivalent and non-interacting binding sites for calcium ions.
The above observations concerning the Lp(a) lipoprotein may be of interest in view of the significantly higher frequency of early coronary heart disease in Lp(a+) than in Lp(a-) individuals, and in view of the previously reported biochemical differences between individuals of different Lp phenotype.     

Genetic lipoprotein variation and lipid levels in man

Analyses of 12 population samples have revealed that the total serum cholesterol level is significantly higher in Lp(a+) than in Lp(a–) individuals. The difference is more pronounced in middle-aged and older people than in young persons, and the difference between Lp(a-h) and Lp(a–) individuals is larger when LDL cholesterol rather than total serum cholesterol is considered. Lp(a –) individuals have a significantly higher triglyceride level than Lp(a +) individuals.
The Lp(a) variation is genetically controlled. Thus, the present study has revealed a small but significant effect of a single, autosomal locus on lipids implicated in atherosclerosis. An association between the phenotype Lp(a +) and coronary heart disease has been demonstrated previously.     

Lp(a) lipoprotein enters cultured fibroblasts independently of the plasma membrane low density lipoprotein receptor

Lp(a) lipoprotein shares the apoB antigen with low density lipoprotein (LDL). The Lp(a) antigen is unique for Lp(a) lipoprotein. Fibroblast association (i.e. plasma membrane binding plus intracellular accumulation), plasma membrane binding, intracellular accumulation and degradation of 125I-Lp(a) lipoprotein were studied in strains from subjects with or without autosomal dominant hypercholesterolemia (HC). Subjects without HC (non-HCs) have cell surface receptors for low density lipoprotein (LDL receptors). On the average, HC heterozygotes have half-normal LDL receptor activity and "receptor-negative" HC homozygous cell strains lack functional receptors. Fibroblast processing of 125I-Lp(a) lipoprotein was compared to fibroblast processing of 125I-LDL. LDL receptor-dependent processing of 125I-LDL was saturated at about 50 microgram apo 125I-LDL.ml-1 in non-HC fibroblasts. 125I-Lp(a) lipoprotein was, however, largely processed independently of receptor mechanisms by non-HC cells (highest concentration examined 150 microgram apo 125I-Lp(a) lipoprotein . ml-1). Lp(a) lipoprotein did not interfere with 125I-LDL for fibroblast association, but inhibited 125I-LDL degradation. The interference with 125I-LDL degradation was time dependent. Only slightly higher 125I-Lp(a) lipoprotein processing values were found in non-HC and HC heterozygous strains than in "receptor-negative" HC homozygous strains. However, non-HC cells had more than tenfold higher 125I-LDL processing values than "receptor-negative" HC homozygous cells.     

Metabolism and clinical significance of lipoprotein Lp(a) (author's transl)

With sensitive methods, the lipoprotein Lp(a) can be demonstrated in the serum of all human subjects, except patients with abetalipoproteinaemia. A high serum level of Lp(a) is considered as a risk factor for atherosclerotic vascular disease (coronary heart disease). The chemical and physical properties of Lp(a) are very similar to those of low density lipoproteins (LDL, Lp-B). In contrast to LDL, Lp(a) has an additional apolipoprotein, the specific Lp(a) antigen. From in vivo studies with 125I-labeled lipoproteins, the following conclusions can be drawn: 1. Lp(a) is not a metabolic product of other apolipoprotein B-containing lipoproteins. Apparently, Lp(a) is synthesized as a separate lipoprotein. 2. Lp(a) is not catabolized to other lipoproteins. Lp(a) leaves the plasma as an intact particle. 3. The fractional catabolic rate and the distribution between the intra- and extravascular compartment are similar for Lp(a) and LDL. 4. The serum level of Lp(a) is primarily determined by the synthetic rate and not by the catabolic rate.     

Serum lipoprotein(A) profiles in a Singaporean population.

Lipoprotein(a) [Lp(a)] is formed when apolipoprotein(a) is linked to low density lipoprotein (LDL)-cholesterol via a single disulfide bond. It is an independent risk factor for myocardial infarction and raised concentrations are associated with an increased risk of developing coronary artery disease. Singapore has a multi-racial population of 77% Chinese, 14% Malays and 7% Indians. Studies have shown that the Indians have significantly higher standardised mortality ratios (SMR) compared to the Chinese and the Malays. We measured serum Lp(a) concentrations in 803 healthy individuals recruited from the Multiphasic Health Screening Programme, using the Macra Lp(a) sandwich enzyme immunoassay kit (Strategics Diagnostics, Delaware, USA). Lp(a) concentrations were skewed in all three groups. Our population mean was 9.0 mg/dl, with 50th, 75th and 95th percentile values of 10.2, 19.8 and 43.1 mg/dl, respectively, which are lower than values reported from Caucasian populations (15.0, 29.0 and 60.0 mg/dl, respectively). Males had lower Lp(a) concentrations than females (P < 0.05). The Indian group had significantly higher concentrations (median 12.3 mg/dl) compared to their Chinese (median 9.6 mg/dl) and Malay (median 8.4 mg/dl) counterparts (P < 0.05). This could partly account for the higher SMR seen in the Indian population in Singapore. As serum Lp(a) concentrations are method- and population-dependent, we recommend that laboratories determine their own reference ranges by their method to avoid misclassification of the coronary heart disease (CHD) risk of patients.