Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a).

Patients with terminal renal insufficiency suffer from an increased incidence of atherosclerotic diseases. Elevated plasma concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases. Variable alleles at the apo(a) gene locus determine to a large extent the Lp(a) concentration in the general population. In addition, other genetic and nongenetic factors also contribute to the plasma concentrations of Lp(a). We therefore investigated Apo(a) phenotypes and Lp(a) plasma concentrations in a large group of patients with end-stage renal disease (ESRD) and in a control group. Lp(a) concentrations were significantly elevated in ESRD patients (20.1 +/- 20.3 mg/dl) as compared with the controls (12.1 +/- 15.5 mg/dl, P < 0.001). However, no difference was found in apo(a) isoform frequency between the ESRD group and the controls. Interestingly, only patients with large size apo(a) isoforms exhibited two- to fourfold elevated levels of Lp(a), whereas the small-size isoforms had similar concentrations in ESRD patients and controls. Beside elevated Lp(a) concentrations, ESRD patients had lower levels of plasma cholesterol and apolipoprotein B. These results show that elevated Lp(a) plasma levels might significantly contribute to the risk for atherosclerotic diseases in ESRD. They further indicate that nongenetic factors related to renal insufficiency or other genes beside the apo(a) structural gene locus must be responsible for the high Lp(a) levels.     

Normal lipoprotein(a) concentrations and apolipoprotein(a) isoforms in patients with insulin-dependent diabetes mellitus

Lipoprotein(a) [Lp(a)] is an LDL particle in which apoliporotein B-100 is attached to a large plasminogen-like protein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated, and plasma Lp(a) concentrations above 20-30 mg dl-1 are an independant risk factor for ischaemic heart disease (IHD). To investigate whether Lp(a) could be important for the high cardiovascular mortality rate in patients with insulin dependent diabetes mellitus (IDDM), we determined Lp(a) concentrations and phenotypes in a group of 108 men (median age 32 years) with IDDM without nephropathy. A group of 40-year-old men (n = 466) served as controls. The median Lp(a) concentration was 7.4 mg dl-1 [95% CI 4.9 to 11.7] in the diabetic patients and 6.3 mg dl-1 [95% CI 5.2 to 7.0] in controls. The Lp(a) concentration exceeded 30 mg dl-1 in 22% of IDDM patients and in 20% of controls (P = 0.13). Moreover, the distribution of apo(a) phenotypes did not differ between patients and control. Lp(a) levels and apo(a) phenotypes are thus apparently the same in IDDM patients without nephropathy and controls. These findings do not exclude the possibility that Lp(a) may be increased in patients with nephropathy in whom coronary artery disease frequently co-exist or that Lp(a) in a given concentration is more atherogenic in IDDM patients than in persons without IDDM.     

Atherogenesis in transgenic mice with human apolipoprotein B and lipoprotein (a).

The engineering of mice that express a human apoB transgene has resulted in animals with high levels of human-like LDL particles and through crosses with human apo(a) transgenics, high levels of human-like lipoprotein (a) (Lp[a]) particles. In this study, these animals have been used to compare the atherogenic properties of apo(a), LDL, and Lp(a). The presence of the high expressing apoB (apoBH) transgene was associated with a 2.5-fold increase in VLDL-LDL cholesterol (primarily in the LDL fraction) and a 15-fold increase in proximal lesions compared with non-transgenic mice (P < or = 0.0001), while the presence of the low expressing human apoB (apoBL) transgene was not associated with major changes in lipoprotein profiles or increases in aortic lesion size. Examination of aortas of apoBH mice demonstrated lesions along the entire length of the aorta and immunochemical analysis of the lesions revealed features characteristically seen in human lesions including the presence of oxidized lipoproteins, macrophages, and immunoglobulins. Unlike animals with the apoBL transgene, animals with the apo(a) transgene had significant increases in proximal aortic fatty streak lesions compared to nontransgenic control animals (threefold; P < 0.02), while animals with both transgenes, the apo(a)/apo BL double transgenics, had lesions 2.5 times greater than animals expressing the apo(a) transgene alone and eightfold (P < 0.0006) greater than nontransgenic animals. These murine studies demonstrate that marked increases in apoB and LDL resulted in atherosclerotic lesions extending down the aorta which resemble human lesions immunochemically and suggest that apo(a) associated with apoB and lipid may result in a more pro-atherogenic state than when apo(a) is free in plasma.     

Relationship between plasma lipoprotein (a), apolipoprotein (a) phenotypes, and other coronary heart disease risk factors in a Melbourne South Asian population

BACKGROUND: High plasma lipoprotein(a) [Lp(a)] level is a strong and important risk factor for cardiovascular disease (CVD). Small-sized apolipoprotein(a) [apo(a)] isoforms (F, B, S1, and S2) are inversely correlated with the high levels of Lp(a) in plasma and significantly associated with CVD. Although the effects of apo(a) phenotypes and various risk factors on Lp(a) status in South Asian population may have been studied in other countries, there are no reports involving these risk factors in Australia. METHODS AND RESULTS: Factors contributing to variation in Lp(a) were surveyed in 402 (216 males and 186 females) South Asian Melburnians. There was a negative relationship between low alcohol beer per day and Lp(a) in men (P < 0.05). Approximately 21% of the variance of Lp(a) concentration in men and 6% in women were explained by age. Age was positively associated with Lp(a) concentrations in men but negatively in women. The most commonly occurring phenotype was apo(a) S3. In this phenotype, Lp(a) concentrations ranged from non-detectable to 811 mg/l. After adjusting for age, an inverse correlation was observed between Lp(a) concentration and apo(a) phenotypes (P < 0.01). CONCLUSIONS: Although Lp(a) has been reported to be genetically determined, there are clearly other factors contributing to variations in Lp(a) concentrations in a South Asian population.     

Interaction of recombinant apolipoprotein(a) and lipoprotein(a) with macrophages.

Elevated plasma levels of lipoprotein(a), Lp(a), represent a major, inherited risk factor for coronary heart disease, although the mechanism of its action remains unknown. Lp(a) is distinguished from the related LDL particle by the addition of apolipoprotein(a), apo(a). The presence of this large glycoprotein is likely to affect the binding of the particle to the LDL receptor and/or other receptors which may contribute to the atherogenic potential of Lp(a). Here we demonstrate the binding to macrophages of Lp(a) and pure recombinant apo(a) protein, via a specific, high-affinity receptor. This binding could lead to foam cell formation and the localization of Lp(a) to atherosclerotic plaques.     

Heterogeneity of lipoprotein Lp(a) and apolipoprotein(a)

We have purified Lp(a) lipoproteins from sera of four subjects by ultracentrifugation, selective precipitation, and chromatofocusing. Each subject had two forms of serum Lp(a) that were separable by chromatofocusing. We purified apolipoprotein (a) [apo(a)] from the eight isolated Lp(a)s and obtained only one form of apo(a) from each subject. The four apo(a)s seen on sodium dodecyl sulfate-polyacrylamide gel electrophoresis had different apparent molecular masses, ranging from 275 to 440 kDa. Chemical deglycosylation of the smallest apo(a) yielded a 235 kDa protein, which may be a core protein structure common to all apo(a)s. We conclude that there are many forms of serum Lp(a) and apo(a). The heterogeneity of serum Lp(a) particles can be ascribed in part to differences in size of apo(a), but other factors must account for the existence within a single patient of different Lp(a)s that contain apparently identical apo(a). One must consider the heterogeneity of Lp(a) when designing assays for this lipoprotein.     

Serum and lipoprotein apolipoprotein B levels in normal subjects and patients with hyperlipoproteinaemia.

Apolipoprotein B (apo B) levels were measured by radioimmunoassay in the serum and lipoproteins from normal subjects and patients with hyperlipoproteinaemia. The total serum apo B concentration in normal subjects was 0.91 +/- 0.16 g/l (mean +/- S.D.); in type IIa hyperlipoproteinaemia it was 2.24 +/- 0.61 g/l; in type IIb, 3.05 +/- 1.24 g/l; in type IV, 2.24 +/- 0.99 g/l; and in type V, 1.30 +/- 0.16 g/l. In normal subjects 5.6 +/- 2.1% (mean +/- S.D.) of total apo B was present in very low density lipoproteins (VLDL) and 93 +/- 9% in low density lipoproteins (LDL). Corresponding values for type IIa were 3.8 +/- 1.9% and 93 +/- 3%, for type IIb, 9.9 +/- 7.5% and 91 +/- 1%, for type IV, 16.9 +/- 9.5% and 81 +/- 9%, and for type V, 38.4 +/- 11.0% and 52 +/- 8%. The ratio of cholesterol to apo B in serum was decreased in types IIa, IIb and IV, and increased in type V whereas the ratio of triglyceride to apo B in serum was decreased in type IIa, normal in type IIb and increased in types IV and V. The ratio of cholesterol to apo B in VLDL was increased in types IIa, IIb and V, but normal in type IV, whereas in LDL, this ratio was normal in types IIa and V but reduced in types IIb and IV. The ratio of triglycerides to apo B in VLDL was normal in types IIa, IIb and IV but raised in type V. In LDL, this ratio was increased in types IIb and IV but normal in types IIa and V.     

Variation in lipoprotein(a) concentration associated with different apolipoprotein(a) alleles.

Plasma lipoprotein(a) (Lp(a)) concentrations vary considerably between individuals. To examine the variation for products of the same and different apolipoprotein(a) (apo(a)) alleles, conditions were established whereby phenotyping immunoblots could be used to estimate the concentration of Lp(a) associated with the constituent apo(a) isoforms. In these studies 28 distinct isoforms were identified, each differing by a single kringle IV unit. Tracking the isoforms through 10 families showed that there could be up to 200-fold difference in the Lp(a) concentration associated with the same-sized isoform produced from different alleles. In contrast there was typically < 2.5-fold variation in the Lp(a) concentration associated with the same allele. However, there were four occasions where the concentration associated with a particular allele was reduced below the typical range from one generation to the next. A nonlinear, inverse trend with isoform size was apparently superimposed upon the other factors that determine Lp(a) concentration. Inheritance of familial hypercholesterolemia or familial-defective apoB100 had little consistent effect upon Lp(a) concentration. In both the families and in other unrelated individuals the distribution of isoforms and their associated concentrations provided evidence for the presence of at least two and possibly more subpopulations of apo(a) alleles with different sizes and expression.     

缺血性脑卒中患者血清氧化脂蛋白(a)水平升高

摘要：目的：观察血清氧化脂蛋白(a)［ox-Lp(a)］水平及其与缺血性脑卒中（CIS）严重程度间的关系。 方法：分别检测93例CIS患者［按美国国立卫生研究院卒中量表（NIHS）评分分为轻型48例,重型45例］,脑出血患者30例和体检健康者48例血清ox-Lp(a)、Lp(a)水平并进行统计学分析。 结果：CIS轻型、重型患者血清ox-Lp(a)（t分别为-2.147、-5.082,P均＜0.05）、Lp(a)（t分别为-2.347、-4.187,P均＜0.05）水平均高于体检健康者,CIS重型患者血清ox-Lp(a)、Lp(a)水平均高于轻型组（t分别为-2.700、-0.231,P均＜0.05）和脑出血组（t分别为4.205、-2.180,P均＜0.05）。CIS患者血清ox-Lp(a)与Lp(a)水平呈正相关（r=0.429,P＜0.01）,与HDL-C水平呈负相关（r=-0.149,P＜0.01）;NIHSS与血清ox-Lp(a)、Lp(a)水平呈正相关（r分别为0.324、0.299,P均＜0.01）。多元线性回归分析显示血清ox-Lp(a)、Lp(a)共同决定了13.6%的NIHSS变化［β分别为0.246、0.243,P均＜0.05;决定系数（R²）=0.136)］。多元Logistic回归分析显示,校正年龄、性别和血脂水平等因素后,高ox-Lp(a)水平是CIS重型组的危险因素［风险比（OR）=1.209,95%可信区间（CI）=1.033~1.414］。 结论: CIS患者血清ox-Lp(a)水平升高,并与疾病严重程度相关。     

Predictors of lipoprotein(a) levels in a European and South Asian population in the Newcastle Heart Project

BACKGROUND: Understanding of the higher susceptibility of South Asians to coronary heart disease is limited. One explanation is the combination of high prevalence of insulin resistance with higher lipoprotein(a) levels. MATERIALS AND METHODS: Lipoprotein(a) levels and genotypes in three South Asian groups aged 25-74 years (Indian, Pakistani, Bangladeshi) were compared with a European population in a cross-sectional study. Biochemical measurements included lipids, apolipoprotein A1 and B, glucose, insulin and fibrinogen. Insulin sensitivity was calculated using the homoeostasis model assessment method (HOMA). RESULTS: There was no significant difference in lipoprotein(a) levels between South Asian and European men. South Asian women combined had higher lipoprotein(a) levels than European women, a difference probably resulting from higher lipoprotein(a) levels in Pakistani women compared with Indian and Bangladeshi women. Fasting insulin and HOMA were negatively associated with Lp(a) in South Asians though the associations were statistically significant only in men. There were only modest associations between most cardiovascular risk factors and Lp(a). Twenty-seven apolipoprotein(a) size alleles were detected in the three South Asian groups ranging from 16 to 43 kringle-IV repeats. The apolipoprotein(a) size polymorphism explained 23% of the variability in lipoprotein(a) levels in South Asians. CONCLUSIONS: There were few nongenetic predictors of lipoprotein(a) levels in South Asians and Europeans. The lack of difference in Lp(a) between the South Asian and European men and the fact that differences between the women seemed to be confined to the Pakistani group offer little support to the hypothesis that higher Lp(a) levels contribute to the increased risk of heart disease in South Asians. Our findings do not support the hypothesis that susceptibility to heart disease in South Asians results from a combination of high insulin resistance and high Lp(a) levels.     

Lack of association between apolipoprotein E genoype and ischaemic stroke in a Scottish population

BACKGROUND: Apolipoprotein E epsilon4 allele has been associated with increased risk of coronary heart disease, and is also a major genetic susceptibility locus for Alzheimer's disease. Some studies have shown an association between apoE genotype and ischaemic stroke or outcome following stroke, while other studies have failed to do so. Materials and methods Using PCR and the Taqman fluorescence system to detect polymorphisms we examined apoE genotype in 266 ischaemic stroke cases and in a control population. RESULTS: We found no association between apoeE epsilon 4 allele distribution and ischaemic stroke, or with outcome following stroke as measured using the Rankin score. Conclusion This study disagrees with a recent meta-analysis, and suggests that further studies are required to clarify the exact relationship between apoE genotype and ischaemic stroke.     

Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.

Human plasma phospholipid transfer protein (PLTP) circulates bound to high density lipoprotein (HDL) and mediates both net transfer and exchange of phospholipids between different lipoproteins. However, its overall function in lipoprotein metabolism is unknown. To assess the effects of increased plasma levels of PLTP, human PLTP transgenic mice were established using the human PLTP gene driven by its natural promoter. One line of PLTP transgenic mice with moderate expression of PLTP mRNA and protein was obtained. The order of human PLTP mRNA expression in tissues was: liver, kidney, brain, small intestine > lung > spleen > heart, adipose tissue. Western blotting using a human PLTP monoclonal antibody revealed authentic human PLTP (Mr 80 kD) in plasma. Plasma PLTP activity was increased by 29% in PLTP transgenic mice. However, plasma lipoprotein analysis, comparing PLTP transgenic mice to control littermates, revealed no significant changes in the plasma lipoprotein lipids or apolipoproteins. Since previous studies have shown that human cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase only function optimally in human apoAI transgenic mice, the human PLTP transgenic mice were cross-bred with human apoAI transgenic mice. In the human apoAI transgenic background, PLTP expression resulted in increased PLTP activity (47%), HDL phospholipid (26%), cholesteryl ester (24%), free cholesterol (37%), and apoAI (22%). There was a major increase of apoAI in prebeta-HDL (56%) and a small increase in alpha-HDL (14%). The size distribution of HDL particles within alpha- and prebeta-migrating species was not changed. The results suggest that PLTP increases the influx of phospholipid and secondarily cholesterol into HDL, leading to an increase in potentially antiatherogenic prebeta-HDL particles.     

Association of lipoprotein(a) and apolipoprotein(a) phenotypes with coronary and carotid atherosclerosis in CHD men

AIM: To evaluate in a case-control cross-sectional study whether lipoprotein(a) concentration and apo(a) phenotypes are associated with the presence and severity of coronary and carotid atherosclerosis. MATERIALS AND METHODS: We have examined 198 male CHD patients (mean age 53 +/- 8) years) with stenosis more than 50% at least in one main coronary artery or its major branches. Duplex scanning was performed in 168 patients to assess the degree of carotid atherosclerosis. Seventy six apparently healthy men (mean age 39 +/- 9 years) formed the control group. Lp(a) concentration was measured by ELISA, apo(a) phenotyping was performed by immunoblotting. RESULTS: Lp(a) level was significantly higher in cases compared to controls: 37 +/- 31 mg/dl vs. 18 +/- 27 mg/dl, p < 0.05. Patients had low-molecular weight apo(a) phenotypes more frequently than controls: 46% vs. 29%, p = 0.01. Patients aged 45 years and younger had low-molecular weight apo(a) phenotypes more frequently than older ones (65% vs. 42%, p < 0.05) and controls (65% vs. 29%, respectively, p = 0.001). High Lp(a) level and low-molecular weight apo(a) phenotypes correlated with presence and number of coronary occlusions. CONCLUSION: There was association between Lp(a) level, low-molecular weight apo(a) phenotypes and presence, severity, extension of carotid atherosclerosis. No differences in distribution of other CHD risk factors among all subgroups of patients were found.     

佐剂性关节炎大鼠载脂蛋白高密度脂蛋白的变化及意义

目的观察佐剂关节炎(AA)大鼠载脂蛋白AI(ApoAI)、高密度脂蛋白(HDL)和血管内皮生长因子(VEGF)、E选择素(E-selection)的变化及相关性研究。方法将27只雄性大鼠随机分为正常组、模型组,分别为模型组15只,正常组12只,用弗氏完全佐剂(CFA)向模型组大鼠右后足跖皮内注射0.1 ml诱发大鼠产生关节炎,观察各组大鼠ApoAI、HDL和VEGF、E选择素的变化,并作相关性分析。结果(1)ApoAI模型组与正常组升高率分别为93.33%和50.00%,HDL模型组与正常组升高率分别为86.67%和41.67%,模型组升高率均显著高于正常组(P<0.05)。与正常组相比,模型组VEGF、E选择素、IL-1β、CRP显著升高(P<0.01或P<0.05);IL-10显著降低(P<0.01)。(2)模型组ApoAI、HDL与VEGF、E选择素、IL-1β呈显著负相关(P<0.05或P<0.01),与足跖肿胀度、关节炎指数、CRP呈显著正相关(P<0.05或P<0.01),与IL-10无明显相关。结论AA大鼠在足跖肿胀的同时出现ApoAI、HDL的升高及血管内皮细胞的损伤,提示免疫应激导致AA大鼠ApoAI、HDL的改变,并与疾病的活动度、细胞因子的紊乱、血管内皮的损伤密切相关。     

肝硬化患者测定血清脂蛋白及载脂蛋白的意义

目的 探讨血清脂蛋白及载脂蛋白测定在肝硬化疾病中的价值。方法 高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)采用酶法(选择遮蔽),载脂蛋白A1(apoA1)、载脂蛋白B100(apoB100)采用免疫透射比浊法。上述项目全部在O-LYMPUS1000全自动生化分析仪上检测。结果 肝硬化失代偿期血清HDL-C、LDL-C、apoA1、apoB100浓度均明显降低,与正常对照组比较有非常显著性差异(P<0.01-0.001)。肝硬化代偿期血清HDL-C及apoA1降低明显,与正常对照组比有显著性差异(P<0.05-0.01),而LDL-C、apoB100下降不明显,与正常对照组比无显著性差异(P>0.05)。结论 肝硬化患者同时检测HDL-C、LDL-C、apoA1及apoB100水平,不仅可以反映肝脏脂蛋白和载脂蛋白合成代谢水平,同时可以判断肝硬化严重程度及预后,对指导临床治疗有一定意义。