高密度脂蛋白抗动脉粥样硬化作用

高密度脂蛋白抗动脉粥样硬化作用刘秉文，曾成林（华西医科大学生物化学与分子生物学研究所成都６１００４１）血浆高密度脂蛋白（ＨＤＬ）的密度为１．０６３～１．２１０，其电泳迁移率处于α－带，又称为α—脂蛋白，主要由肝脏和肠道合成。ＨＤＬ含蛋白质５０％～５５...     

高密度脂蛋白抗动脉粥样硬化的研究现状

高密度脂蛋白抗动脉粥样硬化的研究现状张兴义，赵洁，杨宝田（长春生物制品研究所，长春市中心血站）１高密度脂蛋白预防和治疗动脉硬化性疾病Ｇｏｆｍａｎ提出ＨＤＬ与动脉粥样硬化呈负相关的论断已近半个世纪。这期间不但大量临床资料证明了这个观点的正确性，而且已有...     

高密度脂蛋白功能与动脉粥样硬化

冠心病是东西方各国发病和死亡的第一位原因。冠状动脉粥样硬化是多因素疾病,从危险因素的作用,内皮功能的失调,致动脉粥样硬化脂蛋白滞留于动脉壁,炎症反应,到泡沫细胞和纤维斑块的形成,斑块破裂和血栓形成,构成了冠心病发生、发展和转归的序列过程。在众多的危险因素中,胆固醇升高是具有因果性致病性因子,     

靶向“失功能性”高密度脂蛋白的研究进展

高密度脂蛋白(HDL)是血浆中携运胆固醇的一类主要脂蛋白,正常情况下,HDL具有介导胆固醇逆向转运(RCT)、抗氧化及抗炎、抑血栓形成、促内皮修复等调节血管功能的作用,是机体重要的动脉粥样硬化(As)防御因素。但HDL是在起源、大小、组成及功能上表现极不均一性的脂蛋白颗粒,同时炎症、氧化应激、血脂紊乱、高糖等环境下可引起HDL结构及组分的     

氧化修饰高密度脂蛋白与动脉粥样硬化

血浆高密度脂蛋白 (HDL)与低密度脂蛋白(1DL)一样 ,可以被氧化修饰 ,体内多种因素均具有氧化修饰HDL ,形成氧化修饰的高密度脂蛋白 (ox -HDL)的作用 ,HDL被氧化后化学组成与理化性质发生改变 ,不但失去抗动脉粥样硬化 (AS)的作用 ,反而具有致AS作用。维生素C和维生素E的摄入有可能有助于防止HDL的氧化。     

高密度脂蛋白亚型抗动脉粥样硬化血栓形成的作用机制

高密度脂蛋白胆固醇浓度与冠状动脉粥样硬化发生的危险性呈负相关。血浆高密度脂蛋白是一类颗粒大小不均一的脂蛋白,可分为两个大的亚型,即体大质轻的高密度脂蛋白2和小而密的高密度脂蛋白3。高密度脂蛋白及其载脂蛋白参与抗动脉粥样硬化可能涉及到的机制有:促胆固醇转运,维持内皮完整性,抑制血细胞粘附于血管内皮,抗氧化,抗炎作用,抗血栓和促纤溶等多方面作用。本文主要阐述高密度脂蛋白及其亚型抗血栓形成机制。其主要机制是通过上调内皮一氧化氮合酶表达和促进一氧化氮合酶生成来促进血管保护因子一氧化氮的合成,同时还通过激活前列环素合成,减少组织因子表达,经蛋白C途径下调凝血酶生成,直接或间接地减少血小板聚集,减少凝血和促进纤溶来对抗血栓形成。     

高密度脂蛋白靶向防治动脉粥样硬化新进展

许多随机临床试验已经明确,他汀类药物因为可以降低低密度脂蛋白胆固醇水平并轻度增加高密度脂蛋白胆固醇(HDLC)水平,已经成为防治动脉粥样硬化(As)疾病的主要标准疗法。高密度脂蛋白(HDL)颗粒介导的胆固醇逆转运(RCT)途径具有抗As的作用。目前HDL靶向治疗的重要途径已经不是升高HDLC水平,更多的是通过改善HDL功能,增强血浆胆固醇的清除,以及预防和减轻与As有关的炎症。胆固醇酯转移蛋白抑制剂可增加正常或低HDLC患者的HDLC水平;肝X受体激动剂可通过增加RCT减少As;使用重组HDL的HDL治疗在动物模型中显著有效;在细胞以及动物模型中研究发现,通过干预某些基因靶点,可使HDLC的水平和HDL功能得到改善。回顾相关文献,我们认为:HDL靶向治疗有防治As的潜力,可能对心血管疾病患者有效。     

氧化型高密度脂蛋白与动脉粥样硬化

高密度脂蛋白(HDL)在体内经过髓过氧化物酶氧化形成不同位点修饰的HDL(ox-HDL),ox-HDL通过损伤内皮细胞、影响胆固醇逆转运过程、促进平滑肌增生等方式降低抗动脉粥样硬化的作用。因此HDL不同位点的氧化修饰及相关功能改变或将为治疗动脉粥样硬化提供新的思路。     

内皮脂肪酶与高密度脂蛋白及动脉粥样硬化的关系

高密度脂蛋白具有一定的抗动脉粥样硬化的作用,而内皮脂肪酶可水解高密度脂蛋白,进而影响动脉粥样硬化的进展,故深入探讨三者关系,可能为动脉粥样硬化相关疾病的防治提供崭新的靶点.     

高密度脂蛋白抗动脉粥样硬化的研究进展

低水平的血浆高密度脂蛋白胆固酵(HDL-C)是冠心病的独立危险因子，HDL—C与冠心病的发病呈负相关。高密度脂蛋白(HDL)通过多种机制发挥其抗动脉粥样硬化的作用：它具有抗低密度脂蛋白氧化修饰的作用，减少脂质的摄取沉积；参与胆固醇的逆向转运，促进胆固醇从血管壁排出，将其运送至肝脏清除，并增加粥样硬化斑块的稳定性，减少斑块破裂。此外，它还能保护内皮屏障功能，介导内皮依赖性舒张，并降低粘附分子的表达，具有冠脉保护作用。本文主要阐述HDL抗动脉粥样硬化机制研究的新进展。     

Susceptibility of low- and high-density lipoproteins from diabetic subjects to in vitro oxidative modification.

AIMS: To investigate the hypothesis that lipid peroxidation of both low-density lipoproteins (LDL) and high-density lipoproteins (HDL) is important in the development of atherosclerosis. METHODS: We have investigated whether LDL and HDL from patients with Type 1 diabetes mellitus (DM, n = 16) and Type 2 DM (n = 15) is more susceptible to Cu2+ -induced lipid peroxidation than LDL and HDL from a similar number of nondiabetic controls matched for age, gender and serum cholesterol. RESULTS: The vitamin E content of LDL and HDL from both groups of diabetic patients was not significantly different from controls. The LDL from Type 2 diabetic patients and HDL from both diabetic groups were significantly richer in triglyceride than controls. Phospholipid was decreased in LDL from Type 2 diabetic patients and protein was decreased in HDL in Type 1 DM, but otherwise the composition of LDL and HDL in diabetic subjects was similar to controls. No significant differences were observed in the generation of conjugated dienes or lipid peroxides in either LDL or HDL when the two groups were compared with each other or with their respective controls. CONCLUSIONS: Increased lipid peroxidation occurring in vivo in diabetes is unlikely to be the result of increased susceptibility of lipoproteins to lipid peroxidation, but rather to increased generation of free radicals, to oxidation of lipids other than those present in serum lipoproteins or to decreases in antioxidant systems other than the fat-soluble antioxidants present in lipoproteins.     

Higher level of plasma cholesteryl ester transfer activity from high-density lipoprotein to Apo B-containing lipoproteins in subjects with angiographically detectable coronary artery disease

Background and hypothesis: Plasma high-density lipoprotein cholesterol (HDL-C) levels correlate inversely with the incidence of coronary artery disease. In order to ascertain whether the transfer activity is related to coronary atherosclerosis, we studied plasma cholesteryl ester transfer activity (CETA) from HDL to apo B-containing lipoproteins in a consecutive series of 64 Japanese men aged <60 years who had undergone diagnostic coronary angiography. Methods: The subjects were divided into two groups: those who had ≥50% luminal stenosis in one or more coronary arteries (Group 1) and those who had <50% stenosis (Group 2). Results: CETA was 20.8±6.0%/2h in 38 subjects in Group 1. significantly higher than 17.4±6.9%/2h in 26 subjects in Group 2(p<0.05). Plasma HDL-C levels in Group 1 were significantly lower than those in Group 2(p<0.05). CETA correlated inversely with HDL-C levels (r = ?0.46, p<0.001). Plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and Lp(a) levels did not differ significantly between the two groups. There was no significant correlation between CETA and either LDL-C or TG levels. Conclusion: Results suggest that high CETA is realted to low plasma HDL-C levels and may lead to the development of coronary atherosclerosis. Also, CETA was independent of plasma LDL-C or TG levels.     

内皮脂肪酶与动脉粥样硬化的关系

内皮脂肪酶是脂肪酶家族新成员,最初发现在人脐静脉内皮细胞中表达,主要为磷脂酶活性,参与高密度脂蛋白为主的脂蛋白的代谢,其基因多态性与高密度脂蛋白胆固醇关系密切。内皮脂肪酶主要发挥致动脉粥样硬化功能,调节其表达与活性,可能为防治动脉粥样硬化带来益处。     

Monocyte to high-density lipoprotein ratio presents a linear association with atherosclerosis and nonlinear association with arteriosclerosis in elderly Chinese population: The Northern Shanghai Study

Background and aimsInflammation closely correlates with atherosclerosis and cardiovascular disease (CVD). Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a novel inflammation index that can be obtained by routine blood tests. We aimed to investigate the associations between MHR and atherosclerosis and arteriosclerosis.Methods and resultsWe enrolled 2451 participants from the Northern Shanghai Study. Atherosclerosis (carotid plaque (CP), lower extremity atherosclerotic (LEA) assessed by ankle-brachial index) and arteriosclerosis (arterial stiffness (AS) assessed by carotid-femoral pulse wave velocity) were measured using standard methods. In the univariable logistic regression model, higher MHR was significantly associated with increased AS, CP, and LEA risk. In the multivariable logistic regression model, after adjustment for age, sex, hypertension, diabetes mellitus, body mass index, smoking habit, low-density lipoprotein cholesterol, and family history of premature CVD, quartile 4 (Q4) of MHR was associated with an increased risk of AS (odds ratio (OR) = 1.41; 95% confidence interval (CI):1.05–1.88; P _{for trend} = 0.036), CP (OR = 1.35; 95%CI:1.04–1.77; P _{for trend} = 0.044), and LEA (OR = 2.23; 95%CI:1.49–3.35; P _{for trend}< 0.001). Similar results were observed when MHR was analyzed as a continuous variable. The restricted cubic spline (RCS) curve showed that the association between MHR and AS was nonlinear (P _nonlinear = 0.021), but not LEA (P _nonlinear = 0.177) or CP (P _nonlinear = 0.72).ConclusionMHR presents a linear association with atherosclerosis and a nonlinear association with arteriosclerosis in the elderly Chinese population. These findings may indicate the need for early assessment and intervention for inflammation.The registration number for clinical trials: NCT02368938.     

高密度脂蛋白胆固醇代谢及其对冠心病影响的研究进展

高密度脂蛋白胆固醇的含量与冠心病的发病成反比;除了胆固醇逆转运外,高密度脂蛋白还通过抗炎、抗氧化、抑制血栓形成和改善内皮细胞功能等多种方式参与抗动脉粥样硬化作用;但在某些情况下,高密度脂蛋白的抗动脉粥样硬化作用也会发生改变甚至会出现促进动脉粥样硬化发展的作用。     

高密度脂蛋白——重要而又尚未攻克的靶点

近年来高密度脂蛋白是抗动脉粥样硬化领域的研究热点,高密度脂蛋白通过逆胆固醇转运、抗氧化、抗炎、抗血栓、促纤溶等作用发挥着心血管保护作用,被认为是一个具有锦绣前景的干预治疗靶点。如何提高高密度脂蛋白胆固醇水平和改善高密度脂蛋白的质量与功能,使其更好的发挥心血管保护作用是研究者们关心的热点问题,多种干预高密度脂蛋白功能的新治疗措施的临床试验正在进行中,为冠心病的防治提供新的手段。     

Differential affinity of serum amyloid A1 isotypes for high-density lipoprotein

Serum amyloid A (SAA), a precursor of reactive amyloid deposits, is a multigene product. SAA1, predominant both as an amyloid precursor and in plasma, consists of three allelic variants (SAA1.1, SAA1.3, and SAA1.5). Several investigations have shown that the SAA1.3 allele is associated with susceptibility to AA-amyloidosis in Japanese, and the SAA1.5 allele is related with higher serum concentrations of SAA. However, these results have not been interpreted functionally. This study assessed the affinity of SAA isotypes for high-density lipoprotein (HDL), to which SAA binds in plasma. Using a surface plasmon resonance-based apparatus (BIAcore), the affinity between immobilized recombinant human SAAs and HDL was determined. The SAA concentration was measured in fractions after ultracentrifugation (d?=?1.23) of sera from patients with rheumatoid arthritis, whose SAA1 genotypes were determined. In the BIAcore analysis, as the dissociation reaction under the conditions used was too rapid to fit the typical kinetic model, the steady-state affinity model was used. The affinity (kd) of SAA1.1, SAA1.3, and SAA1.5 for HDL was 1.4?×?10^?5, 1.8?×?10^?5, and 3.7?×?10^?6, respectively. rSAA1.5 showed significantly (p?<?0.05) stronger affinity than the other two. The fraction of lipid-free SAA in serum was significantly (p?<?0.001) lower in the patients with larger numbers of the 1.5 allele at the SAA1 locus. These results suggest that the relatively high affinity of SAA1.5 may cause the high serum concentration and may be related to the low susceptibility to amyloidosis.     

Glycation impairs high-density lipoprotein function

Aims/hypothesis. To examine the effects of incubation of high-density lipoprotein (HDL) under hyperglycaemic conditions on several functions of HDL in vitro.¶Methods. Human HDL (5 mg protein) was incubated for 1 week at 37 °C in the presence or absence of 25 mmol/l glucose. Additional samples of human HDL were incubated in butylated hydroxytoluene to control for oxidation.¶Results. High-density lipoprotein incubated for 1 week in 25 mmol/l glucose had significant increases in the glycation product, fructoselysine and in the advanced glycation end product, N ?-(carboxymethyl)-lysine. High-density lipoprotein apolipoprotein AI and AII concentrations were not altered but glycated HDL had a 65 % reduction in paraoxonase enzymatic activity. Glycated HDL did not inhibit monocyte adhesion to human aortic endothelial cells in response to oxidised low-density lipoprotein in vitro (43 ± 4 monocytes bound vs 21 ± 2 monocytes for control HDL, p < 0.0001). Hepatic lipase-mediated non-esterified fatty acid release from HDL lipids was enhanced in glycated HDL compared with control HDL (25 ± 1 vs 16 ± 1 nmol non-esterified fatty acid hydrolysed/min, respectively, p < 0.0001). Direct glycation of purified paraoxonase protein by incubation in 25 mmol/l glucose caused a 40 % reduction in enzymatic activity. This glycated paraoxonase did not inhibit monocyte adhesion to human aortic endothelial cells in vitro (68 ± 3 monocytes vs 49 ± 2 monocytes bound for control paraoxonase, respectively, p < 0.001). We also measured a 40 % reduction in paraoxonase activity in patients with Type II (non-insulin-dependent) diabetes mellitus and documented coronary artery disease compared with non-diabetic subjects, p < 0.0001.¶Conclusions/interpretation. Alterations in function of HDL caused by exposure to hyperglycaemic conditions could contribute to the accelerated atherosclerosis observed in Type II diabetes. [Diabetologia (2000) 43: 312–320]     

低水平高密度脂蛋白——冠心病独立危险因素

许多临床资料、流行病学研究发现,高密度脂蛋白与冠心病事件的发生率呈负相关,且支持低水平高密度脂蛋白是冠心病的独立危险因素。低水平高密度脂蛋白患者经药物治疗可以明显减少冠心病事件的发生率。