氧化低密度脂蛋白在动脉粥样硬化发病机理中的作用

动脉粥样硬化(atherosclerosis,AS)是一种严重影响人类健康的疾病。特别是心脑血管硬化。在发达国家属于死亡率最高的疾病。近年来,我国心脑血管硬化的发病率也逐年增高。最近的研究表明。低密度脂蛋白(low-density lipopmtein,LDL)在动脉粥样硬化的发生发展中起着非常重要的作用,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。天然的LDL中含有大量不饱和脂肪酸(polyunsaturated fatty acid,PUFA),     

宁夏回族动脉粥样硬化患者外周血LCAT基因DNA甲基化与血脂水平的关系

目的探讨宁夏回族动脉粥样硬化(AS)患者外周血中卵磷脂胆固醇酰基转移酶(LCAT)基因启动子区甲基化水平及与血脂的关系。方法选择经颈部多普勒超声确诊的AS患者35例及正常者42例作为对照组,采用实时荧光定量PCR(qRT-PCR)检测外周血LCAT mRNA的表达,巢式降落式甲基化特异性PCR(nt-MSP)检测外周血LCAT基因DNA启动子区甲基化程度,全自动生化分析仪检测血脂水平。结果 AS组血清TC、TG和LDL水平显著高于对照组(P0.001,P0.001,P0.05);HDL水平低于对照组;与对照组相比,AS组外周血LCAT mRNA表达降低了61.2%(P0.01),同时LCAT基因甲基化程度升高了1.3倍(P0.05)。结论回族AS患者外周血中LCAT DNA高甲基化与AS的发生发展和血脂变化相关。     

高密度脂蛋白受体及其功能

低密度脂蛋白(LDL)受体的存在及其在胆固醇(Ch)代谢和动脉粥样硬化(AS)中的作用已为人们所认识。最近,一些研究表明,具有抗 AS 作用的脂蛋白——高密度脂蛋白(HDL)也可结合至不同组织细胞表     

Urantide对动脉粥样硬化大鼠肝细胞外调节蛋白激酶1/2的作用及机制*

目的:观察Urantide对动脉粥样硬化(AS)大鼠肝中细胞外调节蛋白激酶1/2(ERK1/2)表达的影响,探讨AS大鼠脂肪肝中调控ERK1/2的分子机制。方法:维生素D3(VD3)腹腔注射及特制高脂饲料饮食建立大鼠AS模型,随机分为正常组、AS组、辛伐他汀组、Urantide组。H-E染色观察大鼠胸主动脉、肝的形态学改变;生化检测大鼠血清中总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)的含量;免疫印迹法检测各组大鼠肝组织中尾加压素Ⅱ(UⅡ)、G蛋白偶联受体14(GPR14)、磷酸化ERK1/2(p-ERK1/2)、ERK1/2蛋白质表达水平;免疫荧光法检测各组大鼠肝细胞中p-ERK1/2的表达水平。结果:与正常组相比,AS组大鼠胸主动脉出现典型的AS病理学改变,肝出现典型的脂肪变性;AS组大鼠血清中TC、TG、LDL含量显著升高,HDL含量显著降低;大鼠肝中UⅡ、GPR14、p-ERK1/2、ERK1/2的蛋白表达水平显著升高。与AS组相比,辛伐他汀组及Urantide组大鼠肝的脂肪变性明显减轻;肝中UⅡ、GPR14、p-ERK1/2蛋白表达显著降低,ERK1/2蛋白表达水平无显著变化。结论:Urantide可通过抑制UⅡ/GPR14的生物学效应抑制ERK1/2的活化进而达到治疗脂肪肝的作用。     

内源性高甘油三酯血症患者血浆VLDL、LDL及HDL对血凝的影响

目的：研究内源性高甘油三酯血症(HTG)患血浆极低密度脂蛋白(VLDL)、低密度脂蛋白(LDL)及高密度脂蛋白(HDL)是否发生了氧化修饰及其对血凝的影响。方法：对2l例内源性高甘油三酯血症患与2l例年龄性别相近的正常人的血脂、脂质过氧化物进行了分析。用一次性密度梯度超速离心法分离血浆VLDL、LDL及HDL，测定这三种脂蛋白的234nm光吸收、相对电泳迁移率(REM)和硫代巴比妥酸反应物质(TBARS)，分别将这三种脂蛋白加入由正常人新鲜混合血浆构成的反应系统中，按试剂盒分别测定凝血酶原时间(PT)及活化部分凝血酶原时间(APIT)。结果：内源性HTG患血浆TG含量平均升高2．73倍，HDLC下降l.7l倍，同时LPO升高1．22倍;HTG组VLDL、LDL及HDL的REM、234nm光吸收值、TBARS含量均较对照组显增加(P＜0．01)，表明内源性HTG患血浆VLDL、LDL及LDL均发生了氧化修饰生成Ox—VLDL、Ox-LDL.PT及APTT在分别加入HTG组的VLDL、LDL及HDL后均比加入相应正常组脂蛋白明显缩短(P均＜0．05)。相关分析表明，HTG组血浆VLDL及HDL相对电泳迁移率(REM)与PT呈负相关(P＜0．01)。结论：HTG患血浆VLDL、LDL及HDL发生了氧化修饰，并使PT及APTT明显缩短。     

血浆脂蛋白对血小板功能的影响

脂蛋白和血小板同时与许多疾病的病理过程密切相关,包括动脉粥样硬化(冠心病)、血栓形成等。一般认为,高水的低密度脂蛋白(LDL)和低水平的高密度脂蛋白(HDL)以及血小板的高反应性是这些疾病发生发展的共同危险因素。对于以高水平LDL为特征的家族性Ⅱa型高脂血症患者的研究,更加明显地提示脂蛋白与血小板之间存在直接关系的可能性。来源于Ⅱa型高脂血症患者的血小板对许多生理刺激剂(包括肾上腺素、ADP、凝血酶、胶原等)诱导的聚集、释放以及花生四烯酸代谢的反应性均增高。能够降低血浆脂蛋白(LDL或极低密度脂蛋白VLDL)水平的烟酸和安妥明,同时也能降低Ⅱa型高脂蛋白血症患者的血小板高反应性。这些线索引起了人们对于LDL、HDL与血小板之间的直接关系进行深入探讨的兴趣。     

氧化型低密度脂蛋白受体在动脉粥样硬化发病机制中的作用

正动脉粥样硬化(atherosclerosis,AS)引起的冠心病、脑梗死和外周血管病等疾病,已成为全世界范围内人口死亡的首要原因[1],同时也是以脂质代谢紊乱、内皮不完整、单核-巨噬细胞增生及斑块形成为主要病理特征的慢性疾病[2]。在AS病变演化历程中,氧化型低密度脂蛋白(oxidized low-density lipoprotein,ox LDL)作为关键分子[3],与受体结合后,刺激单核-巨噬细胞摄取大量ox LDL,转变为泡沫细胞,产生大量炎性因子,启动一系列炎症反应,     

阿尔茨海默病患者血脂代谢变化与其疾病发生的关系探讨

目的：分析和探讨阿尔茨海默病患者体内血脂代谢变化情况及其与疾病发生的关系。方法回顾性分析本院2012年02月~2013年08月收治的阿尔茨海默病患者临床资料,测定和比较45例阿尔茨海默病患者以及45例健康人血清甘油三脂(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL)、高密度脂蛋白胆固醇(HDL)以及载脂蛋白A、B水平,并分析和探讨阿尔茨海默病患者血脂代谢变化与其疾病发生的关系。结果45例阿尔茨海默病患者血清中TG、TC、LDL、HDL以及载脂蛋白B平均含量与健康人群相比以上数据均不存在显著性差异,无统计学意义(P>0.05);在载脂蛋白A水平上阿尔茨海默病患者为(1.35±0.20)mmol/L与健康人群的(1.17±0.22)mmol/L相比差异显著,具有统计学意义(P<0.05)。通过线性回归分析可知血清中载脂蛋白A含量与阿尔茨海默病患者疾病严重程度呈正相关。结论研究结果表明,阿尔茨海默病患者血脂中载脂蛋白A的含量显著高于健康人群,进一步探讨发现该病患者的疾病严重程度与血清中载脂蛋白A的含量呈现正相关,因此提示血清中载脂蛋白A含量的升高可能是引起阿尔茨海默病患者发病的重要原因。     

HMGB1/NF-κB通路通过Lp-PLA2介导子痫前期产妇脂质代谢紊乱

目的 探讨HMGB1/NF-κB通路与Lp-PLA2在子痫前期产妇脂质代谢紊乱中的关系及在子痫前期发病中的作用机制.方法 选取妊娠期高血压疾病患者99例、轻度子痫前期孕妇83例、重度子痫前期孕妇112例为病例组.检查各组总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)及低密度脂蛋白胆固醇(low density lipoprotein cholesterin,LDL-C)水平;ELISA检测血清中脂蛋白磷脂酶A(Lipoprotein phospholipase A,Lp-PLA2)水平;Western blot检测各组孕妇胎盘中HMGB1、NF-κB蛋白的表达.结果 子痫前期孕妇TG、TC、LDL水平升高,而HDL水平降低,且血清TG、LDL以及LDL/HDL比值与子痫前期严重程度呈正相关,HDL与子痫前期严重程度呈负相关;子痫前期孕妇血清中Lp-PLA2水平升高,并且与子痫前期严重程度呈正相关,Lp-PLA2水平与TC、TG、LDL呈正相关,与HDL呈负相关;子痫前期孕妇胎盘组织中HMGB1、NF-κB蛋白水平升高,且与Lp-PLA2、TC、TG、LDL呈正相关,与HDL水平呈负相关.结论 HMGB1/NF-B通路的激活增加Lp-PLA2释放,进而调控脂质代谢,促进子痫前期的发生发展.     

Lp(a)与LDL氧化修饰的比较

脂蛋白（a）［Lp（a）］是一种特殊的血浆脂蛋白,其结构、理化性质和脂质组成与低密度脂蛋白（LDL）极为相似。氧化低密度脂蛋白（Ox－LDL）在动脉粥样硬化（AS）的发生、发展中起重要作用,Lp（a）的氧化亦发生于体内动脉壁。在体外,Lp（a）能经铜离子（Cu2＋）介导发生氧化修饰,但与LDL相比,Lp（a）氧化的延迟时间是LDL的1．62倍,氧化速率和氧化程度均只有LDL的63％,故Lp（a）对氧化的敏感性和氧化程度均较LDL为低,其高度致AS作用,难以完全用较高的氧化敏感性来加以解释。     

过氧化物酶体增生物激活受体激活物对ox-LDL诱导内皮细胞c-fos表达的影响

目的 观察过氧化物酶体增生物激活受体α激活物K877对氧化型低密度脂蛋白所诱导的人脐静脉内皮细胞c-fos基因表达的影响及机制。方法 体外培养人脐静脉内皮细胞,采取氧化型低密度脂蛋白刺激,应用K877干预,逆转录聚合酶链反应检测c-fos基因的表达。结果 与对照组比较,氧化型低密度脂蛋白组c-fos基因表达增加（P＜0.05）;与氧化型低密度脂蛋白组比较,K877组c-fos基因表达减少（P＜0.05）;与K877组比较,K877联合多聚肌甘酸c-fos基因表达进一步下降（P＜0.05）。结论 氧化低密度脂蛋白促进了人脐静脉内皮细胞c-fos基因的表达,过氧化物酶体增生物激活受体α激活物K877可抑制c-fos基因的表达,血凝素样氧化型低密度脂蛋白受体1参与了该过程。     

Effects of HDL3 on the expression of matrix-degrading proteases in human endothelial cells

Modified lipoproteins have been suggested to modulate the expression of matrix-degrading proteases in the vascular wall. Since oxidized high density lipoprotein (HDL) has been found in atheromatous plaques and receptors for modified HDL are present on endothelial cells, we investigated the role of native and oxidized HDL3 on the expression of 35 proteases and their inhibitors in human endothelial cells using microarray analysis. Matrix metalloproteinase (MMP)-1, -2, -10, -13 and -14, tissue inhibitor of MMP (TIMP)-1, -2 and -3, cathepsin B and D, and cystatin C were expressed under basal conditions, of which MMP-10 and cystatin C expression have not been described before in endothelial cells. Native HDL3 increased MMP-1 and MMP-14 expression and decreased MMP-13 expression, whereas oxidized HDL3 increased PAI-1 and MMP-1 expression. The expression pattern was confirmed by quantitative real-time PCR. In summary, a large repertoire of matrix-degrading proteases is expressed in endothelial cells, an expression that can be modulated by native and oxidized HDL3.     

Salutary effects of hemodialysis on low-density lipoprotein proinflammatory and high-density lipoprotein anti-inflammatory properties in patient with end-stage renal disease

End-stage renal disease (ESRD) causes oxidative stress, inflammation, low-density lipoprotein (LDL) oxidation, high-density lipoprotein (HDL) deficiency and accelerated atherosclerosis. Uptake of oxidized LDL by macrophages results in foam cell and plaque formation. HDL mitigates atherosclerosis via reverse cholesterol transport and inhibition of LDL oxidation. ESRD heightens LDL inflammatory activity and suppresses HDL anti-inflammatory activity. The effect of hemodialysis on the LDL and HDL inflammatory properties is unknown. By removing the potential pro-oxidant/proinflammatory uremic toxins, dialysis may attenuate LDL inflammatory and HDL anti-inflammatory properties. Conversely, exposure to dialyzer membrane and tubing and influx of impurities from dialysate can intensify LDL and HDL inflammatory activities. This study examined the effect of hemodialysis on LDL and HDL inflammatory activities. Plasma samples were obtained from 12 normal control and 26 ESRD patients before and after hemodialysis with (16 patients) or without (10 patients) heparinization. HDL and LDL were isolated and tested for monocyte chemotactic activity in cultured endothelial cells. ESRD patients had increased LDL chemotactic activity, reduced HDL anti-inflammatory activity, paraoxonase and glutathione peroxidase levels, and elevated plasma IL-6 before dialysis. Hemodialysis partially improved LDL inflammatory and HDL anti-inflammatory activities and enhanced patients' HDL ability to suppress their LDL inflammatory activity. The salutary effect on LDL inflammatory activity was significantly greater in patients dialyzed with than those without heparin. ESRD heightens LDL inflammatory and impairs HDL anti-inflammatory activities. Hemodialysis partially improves LDL and HDL inflammatory activities. The salutary effects of hemodialysis are in part mediated by heparin, which is known to possess lipolytic and antioxidant properties.     

The effect of oestrogen implants on high density lipoproteins and its subfractions in women in their pre-mature menopause

Oestrogen is recognized as having profound effects on lipid and lipoprotein levels. It is also considered as the agent protecting the pre-menopausal woman from arteriosclerotic cardiovascular disease. High density lipoprotein (HDL) has also been ascribed a protective role against the development of arteriosclerosis. The effect of natural oestrogen (17β-oestradiol) administered in the form of a subcutaneous pellet on concentrations of lipids and lipoproteins, particularly high density lipoproteins and its subfractions were determined in three young women with premature menopause. Plasma cholesterol, low density lipoprotein and very low density lipoprotein and very low density lipoprotein levels decreased following oestrogen implantation. High density lipoproteins and in particular subfraction 2 (density cut 1.063-1.125 gm/ml) and subfraction 3 (density cut 1.125-1.21 gm/ml) increased profoundly but there was a slight fall in the HDL 2/HDL 3 cholesterol ratio. The HDL/LDL cholesterol ratio increased from 0.21 to 0.46. A decrease in the urinary FSH levels paralleled these changes in the lipoprotein concentrations. Oestrogen administered in this form, unlike other oestrogen or mixed oestrogen-progestogen compounds is a definite modifier of arteriosclerotic risk, and as such could be given therapeutically in menopausal hypercholesterolemic females.     

Female patients with atrial fibrillation have increased oxidized and glycated lipoprotein properties and lower apolipoprotein A-I expression in HDL

It is well-known that oxidative stress and inflammatory processes are linked to the incidence of atrial fibrillation (AF). In order to provide prognostic biomarkers for AF based on lipoprotein levels, we compared the lipid and protein parameters of oxidation and inflammation in individual lipoproteins from middle-aged females with AF. We analyzed plasma and lipoproteins (VLDL, LDL, HDL2, HDL3) from 11 female patients (mean age, 56±15 years) with paroxysmal lone AF and from a reference group of 10 female patients of similar age (mean age, 54±15 years). The AF group had normal levels of serum lipids and an inflammatory profile, except for a 7.5- and 6-fold elevation in hsCRP and tropoinin?I levels, respectively. No significant differences existed in serum lipids, glucose, uric acid, creatinine and blood urea nitrogen levels between the AF and control groups. The lipoprotein particles from the AF group were more oxidized and glycated with higher triacylglycerol content compared to the control group and the particle size was smaller. The lipoprotein particles from the AF group promoted more foam cell formation via accelerated phagocytosis by macrophages compared to the control group. HDL2 and HDL3 from the AF group showed decreased antioxidant ability and an approximately 30% lower expression of apoA-I compared to the control group. All of these modified properties of lipoproteins, including oxidation and glycation, might be linked to the lower antioxidant ability and elevated inflammatory parameters in women with AF.     

Separation of bovine plasma lipoproteins by a rapid ultracentrifugation method

The recently described method of centrifugation with iodixanol for the rapid separation of human plasma lipoproteins was adapted to separate bovine plasma lipoproteins. Density gradients were generated by mixing plasma with iodixanol 12% (w/v), followed by centrifugation at 350,000 g and 16 degrees C for 3 h 10 min in a vertical rotor. Gradients were unloaded dense-end first into 10 fractions. Human very low density lipoprotein (VLDL; density < 1.011 g/ml), low density lipoprotein (LDL; density = 1.016-1.039 g/ml) and high density lipoprotein (HDL; density = 1.039-1.090 g/ml) were resolved well at densities considerably lower than those traditionally reported in salt gradients. In gradients generated from 12% iodixanol, bovine LDL and HDL exhibited even lower densities (1.016-1.028 and 1.016-1.048 g/ml, respectively) with all lipoproteins occurring at the lower density region of the gradient. In contrast, density gradients generated from layers of equal volumes of 6% and 12% iodixanol readily separated bovine HDL from VLDL, whilst LDL still overlapped with HDL. The latter accounts for >80% of all bovine lipoproteins and exists as two populations, namely light and heavy HDL. Gradients generated from two layers of iodixanol recovered bovine HDL in five fractions. The hypercholesterolaemia associated with lactation resulted in a modest shift in the profile of HDL cholesterol towards lipoprotein particles of lower density (light HDL). Significant between-farm differences were also detected in the density profiles of bovine plasma cholesterol. This new method is suitable for use in research and diagnosis in relation to lipoprotein metabolism disorders in cows.     

Aerobic exercise, lipoproteins, and cardiovascular disease: benefits and possible risks.

Aerobic exercise has been shown to reduce the risk of cardiovascular disease (CVD). This reduction is proportional to the intensity of the exercise. The reduction in CVD risk is at least partially mediated by changes in circulating lipoproteins resulting from adaptive changes in enzymes involved in their metabolism. Specifically, aerobic exercise is associated with reductions in low density lipoprotein (LDL), total cholesterol and triacylglycerol (TAG), and increases in high density lipoprotein (HDL). Exposure to oxygen can oxidatively damage LDL. Oxidized LDL is a risk factor for atherosclerosis. Although aerobic exercise can cause oxidative damage, there are adaptive changes resulting from chronic exercise that result in lower rather than higher levels of oxidized LDL.     

Oxidation of lipoproteins and mechanism of action of antioxidants : contribution of gamma radiolysis]

Water gamma radiolysis leads to a selective and quantitative production of radical species, which allows the study of the one-electron oxidation or reduction of several biological systems, especially lipoproteins. Well defined quantities of*OH, O2*-/HO2* or RO2*. free radicals can thus be specifically produced by radiolysis of water or of ethanol. Such radical species can initiate one-electron oxidation reactions on compounds dissolved in water or in ethanol. Given the oxidative hypothesis of atherosclerosis, it is classically admitted that the oxidation of low density lipoproteins (LDL) but also of high density lipoproteins (HDL) is involved in the development of the atherosclerotic process. Nevertheless, the initiation mechanisms of this oxidation are still poorly defined. Therefore, gamma radiolysis is a method of choice for the study of the mechanisms of oxidation of LDL and HDL by oxygenated free radicals (*OH, O2*-, HO2*, RO2*). Gamma radiolysis allows to obtain oxidized lipoproteins with a very well defined oxidation status, and is a less drastic method than other currently used oxidation procedures such as those using for example copper ions. Finally, gamma radiolysis is also especially appropriate to study the mechanisms of action of antioxidant molecules, either in pure solutions or as inhibitors of lipid peroxidation in lipoproteins in vitro.     

Oxidized high‐density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice

High density lipoprotein (HDL) dysfunction has been widely reported in clinic, and oxidation of HDL (ox‐HDL) was shown to be one of the most common modifications in vivo and participate in the progression of atherosclerosis. But the behind mechanisms are still elusive. In this study, we firstly analyzed and found strong relationship between serum ox‐HDL levels and risk factors of coronary artery diseases in clinic, then the effects of ox‐HDL in initiation and progression of atherosclerosis in LDLR knockout mice were investigated by infusion of ox‐HDL dissolved in chitosan hydrogel before the formation of lesions in vivo. Several new evidence were shown: (i) the serum levels of ox‐HDL peaked early before the formation of lesions in LDLR mice fed with high fat diet similar to oxidative low density lipoprotein, (ii) the formation of atherosclerotic lesions could be accelerated by infusion of ox‐HDL, (iii) the pro‐atherosclerotic effects of ox‐HDL were accompanied by imbalanced levels of effector and regulatory T cells and relative gene expressions, which implied that imbalance of teff and treg might contribute to the pro‐atherosclerosis effects of ox‐HDL.     

Deficiency of hepatic lipase activity in post-heparin plasma in familial hyper-alpha-triglyceridemia

Hyper-alpha-triglyceridemia is a rare dyslipoproteinemia characterized by a pronounced increase in the concentration of triglycerides in the plasma high density lipoprotein (HDL) fraction. One case with this condition, an apparently healthy 61-year-old man, has been studied. Additional lipoprotein abnormalities were present, such as abnormally cholesterol-rich very low density lipoproteins (VLDL) with retarded electrophoretic mobility (beta-VLDL) and triglyceride enrichment of low density lipoproteins (LDL). The patient's plasma concentration of apolipoproteins A-I, A-II and B were normal and those of C-I, C-II, C-III and E were elevated. No abnormal forms of the soluble apolipoproteins of VLDL and high density lipoproteins (HDL) were found after analysis by isoelectric focusing. Lecithin:cholesterol acyltransferase activities, plasma cholesterol esterification rates and lipid transfer protein activities were normal. Post-heparin plasma activity of hepatic lipase was virtually absent and that of lipoprotein lipase was reduced by 50%. In plasma of this patient, HDL was almost exclusively present as large triglyceride-rich particles corresponding in size to particles of the HDL2 density fraction. The only brother of the patient also had hyper-alpha-triglyceridemia together with the other lipoprotein abnormalities described for the index case and deficiency of postheparin plasma activity of hepatic lipase. The findings presented below support the hypothesis that one primary function of hepatic lipase is associated with degradation of plasma HDL2. Deficiency of this enzyme activity thus causes accumulation of HDL2 in plasma leading to hyper-alpha-triglyceridemia. The results further suggest that the abnormal chemical and electrophoretic properties of VLDL and LDL in plasma from the patient, reminiscent of type III hyperlipoproteinemia, are secondary to the lack of the action of hepatic lipase on the HDL particles.