前蛋白转化酶枯草溶菌素9抑制剂的研究进展

胆固醇尤其是低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)升高,是冠心病发病的独立危险因素。降低LDL-C被视为降低冠心病风险的关键因素。前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)通过调控低密度脂蛋白受体影响LDL-C代谢,降低LDL-C水平,成为高胆固醇血症患者治疗的新靶点。因而多种PCSK9抑制剂应运而生。目前已探索了不同途径的PCSK9抑制剂,其中单克隆抗体发展最为迅速,可能将成为一类非常有前景的调脂药物。     

PCSK9抑制剂在动脉粥样硬化性心血管疾病中的抗炎作用研究进展

高脂血症是动脉粥样硬化性心血管疾病（ASCVD）的重要危险因素,降脂治疗是ASCVD治疗的重要内容。近些年来,前蛋白转化酶枯草溶菌素 9（proprotein convertase subtilisin/kexintype9,PCSK9）抑制剂被证实具有强效的降低低密度脂蛋白胆固醇（low density lipoprotein cholesterol,LDL-C）的作用,并被多个降脂指南推荐作为降脂治疗的重要方法。随着研究的深入,PCSK9抑制剂除具有降低LDL-C作用外,还发挥一定程度的抗炎作用。本文从PCSK9参与炎症反应角度出发,对PCSK9抑制剂在ASCVD中的抗炎作用作一综述。     

前蛋白转化酶枯草溶菌素9变异、低密度脂蛋白胆固醇与神经认知功能损害的关系

<正>尽管之前的研究引发了对抑制前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type9,PCSK9)造成神经认知功能损害事件的关注,但近期一个第3期随机试验并没有发现药物性PCSK9抑制与神经认知损害有关。能导致终生低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平降低的PCSK9功能丧失(loss-of-function,LOF)基因变异可为低LDL-C对神经认知损害和减退的潜在     

前蛋白酶转化酶枯草溶菌素9:动脉粥样硬化性心血管疾病防治新靶点

前蛋白转化酶枯草溶菌素9(PCSK9)是近年来新发现的一种前蛋白转化酶,主要通过介导肝细胞表面低密度脂蛋白受体(LDL-R)的降解,升高血浆低密度脂蛋白胆固醇(LDL-C)水平。血浆LDL-C与动脉粥样硬化性心血管疾病(ASCVD)的发生发展密切相关。近年有研究发现,PCSK9还参与脂质代谢外的致动脉粥样硬化(AS)机制。     

PCSK9免疫治疗降低胆固醇研究进展

前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)在调节胆固醇体内平衡中起重要作用,通过与肝细胞表面的低密度脂蛋白受体(LDLR)结合,促进其降解,从而导致血浆低密度脂蛋白胆固醇(LDL-C)浓度升高。PCSK9已成为近年来治疗高胆固醇血症及动脉粥样硬化性心血管疾病(ASCVD)最火热的靶点。本文主要介绍PCSK9免疫治疗降低胆固醇及其对胆固醇代谢影响的研究进展。     

前蛋白转化酶枯草溶菌素9相关影响因素及其抑制剂的研究进展

正前蛋白转化酶枯草溶菌素9(prorotein convertase subtilisin/kexin type 9,PCSK9)是一种分泌型丝氨酸蛋白酶,与低密度脂蛋白受体(LDLR)结合,使肝细胞表面LDLR减少,进而使肝细胞对LDL-C颗粒清除能力下降,血浆LDL-C水平升高,导致动脉粥样硬化的发生和发展,促进心脑血管事件的发生。PCSK9抑制剂的一系列临床试验结果提示,     

前蛋白转化酶枯草溶菌素9在动脉粥样硬化中促炎作用的研究进展

正动脉粥样硬化(atherosclerosis, As)是动脉壁的慢性炎症性疾病,是心血管事件各种原因中常见的病理变化。炎症反应涉及As的各个阶段,其特征是各种炎症细胞和大量炎症介质的相互作用。前蛋白转化酶枯草溶菌素9 (proprotein convertase subtilisin/kexin Type9,PCSK9)是由人1号染色体p32.3上的PCSK9基因编码的一种蛋白酶, 主要来源于人体肝细胞。PCSK9通过促进溶酶体降解肝脏低密度脂蛋白受体(low-density lipoprotein receptor,LDL-R),     

前蛋白转化酶枯草溶菌素9抑制剂对血脂代谢作用的研究进展

家族性高胆固醇血症(FH)因其血脂水平明显增高,引发动脉粥样硬化及心血管事件。前蛋白转化酶枯草溶菌素9(PCSK9)可通过诱导低密度脂蛋白受体内化降解来调节低密度脂蛋白胆固醇(LDL-C)代谢。PCSK9抑制剂通过调节PCSK9水平使LDL-C显著降低,从而为FH患者带来获益。     

降脂新药PCSK9抑制剂研究现状

前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin 9,PCSK9)是由肝脏合成的蛋白酶[1].该酶经分子内自身催化切开后分泌入血,与肝细胞表面低密度脂蛋白受体(LDLR)结合,促进LDLR降解,致使低密度脂蛋白胆同醇(LDL-C)水平升高.同时一系列体外和在体研究均证明PCSK9可促进肝脏LDLR的降解[2].目前,大量的基础研究和临床试验结果表明,外源性干预措施抑制PCSK9活性后,可加速血浆低密度脂蛋白(LDL)清除,从而产生良好的降脂效果.因此,PCSK9抑制剂很可能将是治疗血脂紊乱及相关心血管疾病的新一代药物,现就抑制PCSK9的方法和研究进展进行综述.     

PCSK9抑制剂研究进展

前蛋白转化酶枯草溶菌素9(PCSK9)可诱导低密度脂蛋白受体(LDLR)降解,阻碍血浆低密度脂蛋白胆固醇(LDL-C)向溶酶体的转运,使其在血浆中浓度升高。因而抑制PCSK9可显著降低血浆LDL-C水平,PCSK9抑制剂应运而生。最近ACC 2017(Annual Scientific Session,2017)公布的FOURIER试验结果令人瞩目,使PCSK9抑制剂成为研究热点。本文从PCSK9结构及功能机制、PCSK9抑制剂研究现状和最新临床研究等方面综述PCSK9抑制剂的研究进展。     

PCSK9抑制剂在治疗动脉粥样硬化中的研究进展

人前蛋白转化酶枯草溶菌素9(PCSK9)是一种丝氨酸蛋白酶,可诱导低密度脂蛋白受体的降解,升高血浆低密度脂蛋白胆固醇水平,参与多种促动脉粥样硬化机制。多项临床试验证实,PCSK9抑制剂具有潜在的抗炎、抗血小板、稳定动脉粥样硬化斑块等作用。文章从PCSK9的结构、调控因子、PCSK9抑制剂治疗动脉粥样硬化等方面综述PCSK9及PCSK9抑制剂的相关研究进展。     

Dyslipidemia in rat fed with high-fat diet is not associated with PCSK9-LDL- receptor pathway but ageing

Background Obesity is associated with unfavorable alternations in plasma lipid profile and a broad spectrum of cardio-metabolic disorders. Proprotein convestase subtilisin kexin type 9 (PCSK9) is a novel circulating protein that promotes hypercholesterolemia by decreasing hepatic low lipoprotein density receptor (LDLR) protein. However, the relationship between PCSK9 concentration and lipid profile in an obesity condition has less been investigated. Objective To examine the changes of plasma PCSK9 concentration in a rat model fed with high fat diet (HFD) and its correlation to lipid profile, body weight and ageing. Methods Twenty male Sprague Dawley (SD) rats were divided into two groups, control group (fed with normal pellet for 4 weeks), and high-fat diet group (fed with 3% cholesterol enrich diet for 4 weeks). Blood samples of rats were obtained before and at days 14, 21, and 28 in both groups. The body weight, plasma metabolic parameters (glucose, lipid profile) and PCSK9 were determined at indicated time points. Results The body weights were significantly increased in rats fed with HFD compared to that in rats with normal pellets at day 28. Additionally, total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C) levels in rat fed with HFD were also higher than that in rats fed with control diet while decreased high density lipoprotein cholesterol (HDL-C) levels were found in rats with HFD at day 28. More interesting, there were no differences of plasma PCSK9 concentrations as well as hepatic expression of LDLR between the two groups at day 28. Conclusions Although the body weight and LDL-C were significantly increased in rats fed with HFD at 4 weeks, there were no differences of changes in plasma PCSK9 concentration and LDLR expression of liver tissue in both groups at baseline and day 28, suggesting that dyslipidemia in the rat model with HFD appears not to be associated with PCSK9-LDLR pathway but ageing.     

E670G polymorphism of PCSK9 gene of patients with coronary heart disease among Han population in Hainan and three provinces in the northeast of China

Objective: To investigate the correlation between E670 G polymorphism of proprotein convertase subtilisin/kexin type 9(PCSK9) gene and coronary heart disease(CHD), and contrastively study the regional differences of E670 G polymorphism of PCSK9 gene between patients with CHD among the Han population in Hainan and three provinces in the northeast of China(TPNC), providing scientific basis for prevention and treatment of patients with CHD in different regions. Methods: A total of 233 cases of patients with CHD were selected from the Han population in Hainan and TPNC as the experimental group(118 cases from Hainan, 115 cases from TPNC), and 239 cases with non-CHD were selected among the Han population also in the two regions as control group(125 cases from Hainan, 114 cases from TPNC). The triglyceride(TG), total cholesterol(TC), high density lipoprotein cholesterol and low density lipoprotein cholesterol(LDL-C) levels of plasma were tested and PCR-RFLP method was used to test the E670 G polymorphism of PCSK9 gene. The statistical software package SPSS 21.0 was used for the statistical analysis and P0.05 was considered as statistically significant. Results: The levels of systolic pressure, diastolic blood pressure, fasting blood sugar, TC, TG, and LDL-C of patients in CHD group were significantly higher than those in non-CHD group, while the high density lipoprotein cholesterol level was lower than that in non-CHD group(P0.05). In CHD group, the frequencies of AG, GG genotypes of PCSK9 gene and G allele were higher than those in non-CHD group(P0.05), and in CHD group, the frequencies of AG, GG genotypes and G allele of patients both in Hainan and TPNC were higher than those in control group(P0.05). Among the patients with CHD, the frequencies of GG genotype and G allele of patients in Hainan were lower than those in TPNC(P0.05), and in CHD group, the levels of TG, TC and LDL-C of GG genotype were higher than those of AA genotype(P0.05). While in non-CHD group, there were no significant differences between the frequencies of GG genotype and G allele of patients in Hainan and TPNC(P0.05). Conclusions: There was a close correlation between the E670 G polymorphism of PCSK9 gene and CHD with serum lipid level. Among Han population in Hainan and TPNC, the E670 G polymorphism of PCSK9 gene of patients with CHD exhibited regional differences.     

Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population

The aim of this study was to investigate whether plasma low-density lipoprotein cholesterol (LDL-C) levels in the general population are influenced by rare sequence variations in the PCSK9 gene. We sequenced the promoter and coding regions of the PCSK9 gene in individuals from the general population (n=3655) with the lowest (n=78) and highest (n=96) LDL-C levels and in individuals taking antihypercholesterolemia medication (n=96). We identified 33 sequence variants in the PCSK9 gene among which 24 were specific for Japanese. Statistical analysis showed that one missense mutation, R93C, was associated with low LDL-C levels. The other variants had no association with LDL-C levels or the numbers of individuals with the variants were too small for statistical analysis. A comparison of the numbers of individuals with nonsynonymous mutations between the low LDL-C and high LDL-C/treatment groups found that four missense mutations and one nonsense mutation were identified only in the low LDL-C group and six missense mutations were identified only in the high LDL-C/treatment group. As we have analyzed groups at opposite ends of the LDL-C spectrum, it is likely that some of these nonsynonymous mutations may be associated with either low or high LDL-C in the Japanese population. Based on the extremely high frequencies of the nonsynonymous mutations in PCSK9 compared with those of LDLR or apoB-100, PCSK9 mutations could be important factors that cumulatively influence plasma LDL-C levels in the general population.     

PCSK9在多囊卵巢综合征卵巢颗粒细胞中的表达研究

目的研究前蛋白转化酶枯草溶菌素9(PCSK9)在多囊卵巢综合征(PCOS)卵巢颗粒细胞中的表达情况,并探讨PCSK9表达与PCOS卵巢组织以及睾酮处理的KGN细胞中脂质状况的关系。方法通过来曲唑联合高脂饲料喂养构建PCOS大鼠模型,油红O染色观察PCOS大鼠卵巢组织中脂质分布情况;生物信息学分析筛选PCOS卵巢与正常卵巢转录组数据中参与脂质代谢通路的差异表达基因;采用免疫组织化学和Western blot技术检测PCSK9蛋白在PCOS卵巢组织中的表达情况;采用免疫荧光、qRT-PCR和Western blot技术检测不同浓度睾酮处理的KGN细胞中PCSK9和低密度脂蛋白受体(LDLR)的表达差异;免疫荧光显微镜观察KGN细胞对Dil-LDL的摄取能力。结果油红O染色结果显示PCOS卵巢组织中颗粒细胞上的脂滴分布较正常卵巢组织明显减少;生物信息学分析结果显示PCOS大鼠卵巢组织中上调的PCSK9主要参与胆固醇代谢通路;免疫组织化学和Western blot结果显示PCSK9蛋白主要定位于颗粒细胞且在PCOS大鼠颗粒细胞中表达增加;免疫荧光、qRT-PCR和Western blot结果显示KGN细胞中PCSK9的表达随睾酮浓度的增加而增加,LDLR的表达随睾酮浓度的增加而减少;睾酮(100 nmol/L)可减弱KGN细胞对Dil-LDL的摄取能力。结论 PCSK9在PCOS卵巢颗粒细胞中高表达,其可导致LDLR蛋白表达降低,使颗粒细胞脂质摄取不足。     

前蛋白转化酶枯草溶菌素9抑制剂与血小板功能

前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂能显著地降低血浆低密度脂蛋白胆固醇水平,是高脂血症治疗和高危心血管疾病患者二级预防有潜力的手段。越来越多的证据表明,PCSK9抑制剂降低心血管事件的作用可能部分归因于其对血小板功能的影响。PCSK9抑制剂既可通过抑制PCSK9直接降低血小板功能,也可通过调节脂质水平间接降低血小板功能。PCSK9抑制剂对血小板高反应性的改善以及在缺血性心血管疾病急性期的保护作用是值得研究的方向。     

Einfluss der Lipidstoffwechselparameter auf die Entstehung und Progression der koronaren Herzerkrankung

Disorders of lipid metabolism play a major role in the development and progression of coronary artery disease. Dyslipidemia therefore plays a central role in therapeutic approaches for prevention and treatment of cardiovascular events associated with coronary artery disease. Epidemiological studies have shown an association between various lipid metabolism parameters, the risk of developing coronary artery disease and progression of a pre-existing disease. In particular, increased levels of low-density lipoprotein cholesterol (LDL-C), reduced levels of HDL cholesterol (HDL-C), as well as high levels of triglycerides and increased lipoprotein(a) [Lp(a)] levels can be taken into account when assessing the risk stratification of patients for primary prevention of coronary artery disease. Lifestyle and dietary changes, intensified statin therapy and possibly the addition of ezetimibe remain the major interventions in both primary and secondary prevention of coronary artery disease, as they improve the prognosis particularly by lowering levels of LDL-C. Recently, genetic studies have contributed to extending our understanding of the relationship between lipid metabolism and coronary artery disease. A causal role for progression of coronary artery disease could be demonstrated for LDL-C, Lpa and triglyceride-rich lipoproteins (TRL), which could not be demonstrated for HDL-C in various studies. Furthermore, the effect of reduction of LDL-C by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and by the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib on cardiovascular events is currently being investigated in large clinical outcome study programs.     

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance,Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of low-density lipoprotein (LDL) receptor processing. Evolocumab and alirocumab are PCSK9 inhibitors; however, little is known about the association between PCSK9 levels and lipid profiles in a general population. Because PCSK9 inhibitors have LDL-C lowering effects, we investigated whether there is a positive correlation between serum PCSK9 levels and LDL-C or lipoprotein(a) [Lp(a)].Methods: In Uku town, 674 residents (mean age; 69.2 ± 8.3 years) received health check-ups. The participants underwent a physical examination and blood tests, including PCSK9 and Lp(a). Serum PCSK9 and Lp(a) were measured by ELISA and Latex methods, respectively. HOMA-IR was calculated by fasting plasma glucose × insulin levels/405.Results: The mean (range) of PCSK9 and Lp(a) were 211.2 (49–601) ng/mL and 60 (1–107) mg/dL, respectively. Because of a skewed distribution, the log-transformed values were used. With univariate linear regression analysis, PCSK9 levels were associated with Lp(a) (p = 0.028), triglycerides (p < 0.001), and HOMA-IR (p < 0.001), but not with LDL-C (p = 0.138) levels. Multiple stepwise regression analysis revealed that serum PCSK9 levels were independently associated with triglycerides (p < 0.001), Lp(a) (p = 0.033) and HOMA-IR (p = 0.041).Conclusions: PCSK-9 is independently associated with triglycerides, Lp(a) levels, and HOMA-IR, but not LDL-C, in a relatively large general population sample.     

Attainment of Recommended Lipid Targets in Patients With Familial Hypercholesterolemia: Real-World Experience With PCSK9 Inhibitors

Background

Familial hypercholesterolemia (FH) is the most common inherited dyslipidemia and is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and markedly increased risk for atherosclerotic cardiovascular disease. Lipid-lowering therapy is the mainstay of treatment, but few patients with FH are able to achieve commonly recommended lipid targets.