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。     

PCSK9基因多态性与心血管疾病相关性的研究进展

前蛋白转化酶枯草溶菌素-9(PCSK9)能通过调节细胞膜表面低密度脂蛋白受体,影响血脂代谢,并参与动脉粥样硬化过程。近年来研究表明,PCSK9基因多态性可能与血脂异常及心血管疾病有关。现就PCSK9基因多态性与心血管疾病的研究进展做一综述。     

前蛋白转化酶枯草溶菌素9的相关研究进展

前蛋白转化酶枯草溶菌素9(Proprotein convertase subtilisin/kexin type 9,PCSK9)基因是前蛋白转化酶中的一种,与胆固醇代谢息息相关的基因,是影响心脑血管疾病的重要因子,近年来关于PCSK9的研究逐渐增多,其生物学效应及在疾病中的作用日益受到关注。目前诸多研究证实PCSK9参与多种机体重要的功能,主要包括调节胆固醇代谢,促进肝脏再生,影响神经细胞凋亡,参与炎症反应等。本文就PCSK9在组织及器官上的表达和作用以及其与炎症反应和心肌梗死的关系做一综述。     

前蛋白转化酶枯草溶菌素9基因与脂质代谢

<正>1前蛋白转化酶枯草溶菌素9(PCSK9)简介Seidah等〔1〕在研究神经元发育分化时发现一个新基因,称为PCSK9,该基因编码是一种前蛋白转化酶,名为神经细胞凋亡调节转化酶1(NARC)-1,该酶参与肝细胞发育再生和神经细胞分化〔1〕。后续研究发现,PCSK9蛋白能靶向降解低密度脂蛋白(LDL)受体(LDLR),与脂质代谢、异常胆固醇血症及动脉粥样硬化等有密切关系。     

Evolocumab治疗高脂血症的研究进展

<正>HMG-CoA还原酶抑制剂(他汀类药物)给药降低低密度脂蛋白胆固醇(LDL-C)是当代降低动脉粥样硬化性血管疾病发病率和死亡率的策略的一个重要组成部分,然而如何解决其治疗过程中的不耐受性始终是一个难题~([1])。evolocumab作为一种最新研制的前蛋白转化酶枯草溶菌素(PCSK9)抑制剂,在最近的临床试验中表现出较好的临床结果与研究价值。1 PCSK9的组成PCSK9基因被发现主要是在成人肝细胞表达,PCSK9基因     

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。     

PCSK9促进动脉粥样硬化的机制进展

动脉粥样硬化（atherosclerosis,AS）是心脑血管疾病的重要病理基础。前蛋白转化酶枯草杆菌素/kexin9型（proprotein convertase subtilisin/kexin type9,PCSK9）是前蛋白转化酶家族中的一种,通过将肝细胞表面的低密度脂蛋白受体（low density lipoprotein receptor,LDL-R）介导到溶酶体中被降解,来参与体内低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)的代谢,使循环中LDL-C的水平升高,进而导致AS的发生发展。近年来研究显示,PCSK9可以在不影响血脂的情况下加速AS的发展。也就是说,PCSK9除了调节血脂代谢,还有独立的促进AS进展的机制。本文对PCSK9促AS的作用机制进行综述。     

黑龙江省东部地区汉族人群PCSK9基因第8、9外显子多态性与冠心病的相关性

目的揭示前蛋白转化酶枯草溶菌素(PCSK)9基因第8、9外显子多态性突变位点与冠心病(CHD)的关系。方法选取经冠脉血管造影(CAG)确诊CHD者为CHD组共303例,非CHD者为对照组共233例。收集两组一般资料及临床资料,并记录入院后大生化数据(如血脂、血糖)。采用聚合酶链反应(PCR)对所提取的DNA基因组中PCSK9基因第8、9外显子扩增,测序,确定PCSK9第8、9外显子单核苷酸多态性(SNP)形式及突变频率,揭示其与低密度脂蛋白胆固醇(LDL-C)浓度的关系。结果在黑龙江省东部地区汉族人群中,未发现PCSK9基因第8外显子的突变位点,在第9外显子的筛查中共发现3个突变位点:c.477 T>C、c.604 C>T、c.606 C>T。对照组基因位点c.477 T>C突变患者血清LDL-C浓度水平与非突变者相比无明显变化(P>0.05)。CHD组基因位点c.604 C>T突变患者血清LDL-C浓度水平与非突变患者比较存在明显差异(P<0.05);基因位点c.606 C>T突变患者的血清LDL-C浓度水平与非突变患者相比无明显变化(P>0.05)。结论在黑龙江省东部地区汉族人群PCSK9基因第9外显子的c.604 C>T突变与CHD存在相关性。     

黑龙江省东部地区汉族人群PCSK9基因第1外显子多态性与脂代谢的相关性

目的 研究黑龙江省东部地区汉族人群前蛋白转化酶枯草溶菌素(PCSK)9基因第1外显子多态性与脂代谢的相关性.方法 因心绞痛和(或)运动试验阳性及有冠脉管腔狭窄证据而需入院行冠状动脉造影者220例中,110例冠心病(CHD)者为病例组,110例非CHD者为对照组,检测PCSK9基因第1外显子基因多态性及血脂水平,并对基因多态性与血脂水平进行相关性分析.结果 共发现c.121C>G、c.299C>T、c.427-428insGCT、A53V、P56S和c.556A>G 6个突变位点,其中在A53V突变位点上发现CC和TC两种基因型,但未发现TT基因型.病例组和对照组各基因型间血清三酰甘油(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)水平差异具有统计学意义(P<0.05).病例组中TC基因型血清TG、TC和LDL-C水平均显著高于CC基因型(P<0.05);对照组中TC基因型血清TC水平显著高于CC基因型(P<0.05).结论 PCSK9基因第1外显子在黑龙江省东部地区汉族人群中存在多态性,且与CHD患者脂代谢有关.     

前蛋白转化酶枯草杆菌蛋白酶kexin-9在肾病综合征相关性高胆固醇血症中的作用

正肾病综合征中,肾脏足细胞损害可导致严重的高胆固醇血症,迫切需要新的治疗方法。前蛋白转化酶枯草杆菌蛋白酶kexin-9(proprotein convertase subtilisin/kexin type 9,PCSK9)逐渐成为血浆总胆固醇水平和治疗目标的重要调节因子。该研究旨在验证PCSK9     

The Influence of <Emphasis Type="Italic">PCSK9</Emphasis> Polymorphisms on Serum Low-Density Lipoprotein Cholesterol and Risk of Atherosclerosis

Pro-protein-convertase-subtilisin-kexin-9 (PCSK9) enhances the degradation of the low-density lipoprotein receptor (LDLR) that plays a major role in cholesterol homeostasis. Recent advances have revealed a large number of genetic variants of PCSK9 that may modulate plasma cholesterol levels either positively or negatively, therefore influencing the risk of atherosclerosis. Recognition of these mutants may have clinical implication in assessing severity of disease, prognosis, or response to drug therapy. PCSK9’s expression, secretion, and plasma levels maybe modulated by the proprotein convertase furin, by natural inhibitors (annexin-A2), or influenced by lipid-altering agents such as statins, fibrates, ezetimibe, and berberine. It is now a prime target for therapy, prompting the development of various approaches to reduce its LDLR degrading activity, including antibody neutralization, anti-sense oligonucleotides such as phosphorothioates, locked nucleic acids, and RNA interference, and eventually small molecule inhibitors. Which one will be clinically applicable will depend on long-term effects, cost, and ease of administration.     

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。     

前蛋白转化酶枯草溶菌素9与心肌梗死之间关系的研究进展

前蛋白转化酶枯草溶菌素9(PCSK9)是一类前蛋白转化酶家族蛋白酶K亚家族成员,可以和低密度脂蛋白受体(LDLR)结合,阻抑了LDLR的重复利用,导致肝细胞表面LDLR减少,使外周血中低密度脂蛋白胆固醇(LDLC)水平增加,从而导致血脂代谢异常等一系列病理生理过程。目前研究表明PCSK9与心肌梗死存在一定的相关性,并可能通过独立于LDLC之外的途径调控心肌梗死的发生发展。本文就PCSK9与心肌梗死的相关研究进展进行综述。     

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。     

The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis

The LDL receptor (LDLR) plays an essential role in the regulation of plasma (LDL) cholesterol concentrations by virtue of its ability to clear plasma LDL. Down‐regulation of the LDLR by proprotein convertase subtilisin/kexin 9 (PCSK9) has recently emerged as a regulatory mechanism that controls plasma LDL cholesterol concentrations. Studies in which PCSK9 is over‐expressed in mice, have demonstrated that PCSK9, by enhancing hepatic LDLR degradation, decreases the availability of the LDLR for LDL uptake, resulting in increased plasma LDL cholesterol levels. However, PCSK9 has also recently been shown to mediate down‐regulation of surface receptors other than the LDLR, suggesting that it may have much broader roles than initially thought.     

PCSK9 − „missing link“ der familiären Hypercholesterinämie

Lowering plasma low-density lipoprotein cholesterol (LDL-C) levels to individual therapeutic goals is one of the most effective measures for the prevention of cardiovascular disease. Besides dietary measures, this can be achieved pharmaceutically by inhibition of hepatic cholesterol synthesis with statins or inhibition of intestinal cholesterol absorption (e.g., ezetimibe and bile acid sequestrants). Decisive for lowering LDL is an increased hepatic uptake of circulating LDL via an increase in LDL receptors (LDLR) in hepatic cell membranes. The formation of new LDLR and recirculation of existing LDLR play a decisive role in this process. An important modulator of LDLR is proprotein convertase subtilisin/kexin type 9 (PCSK9). In the last years genetic studies have identified several mutations in the PCSK9 gene leading to a gain of function and carriers of these mutations suffer from autosomal dominant hypercholesterolemia. In contrast, carriers of PCSK9 loss of function mutations show very low plasma LDL-C concentrations and a markedly reduced risk for coronary artery disease. These fundamental discoveries have sparked the development of a completely novel therapeutic approach to treating hypercholesterolemia. At present, inhibition of PCSK9 by monoclonal antibodies presents the most promising therapeutic approach. First human antibodies were recently approved as the first immunotherapeutic agents for the treatment of severe hypercholesterolemia and in patients with statin intolerance. An additional PCSK9 antibody is presently being studied in phase III clinical trials.     

前蛋白转化酶枯草溶菌素9抑制剂的临床研究及应用进展

前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂可通过抑制肝细胞表面低密度脂蛋白受体的降解对脂质代谢起到调节作用。目前已有多项临床研究证明,PCSK9抑制剂单一药物或与他汀类药物联合使用可显著降低低密度脂蛋白胆固醇水平。本文综述了当前PCSK9抑制剂的重要临床研究及应用进展,并简要总结了常见PCSK9抑制剂的安全性、有效性及临床应用现状。     

PCSK9 als neues Target in der Therapie der Hypercholesterinämie

Proprotein convertase subtilisin/kexin type 9 (PCSK 9) is a key regulator of cholesterol homeostasis acting via degradation of the low density lipoprotein (LDL) receptor. Loss of function PCSK 9 mutations result in very low LDL cholesterol serum levels and protection from cardiovascular disease whereas gain of function mutations increase serum LDL cholesterol. Based on in vitro and in vivo data antibodies targeting PCSK 9 have now emerged as a novel treatment option in patients with cardiovascular disease. This review briefly summarizes the biochemistry and function of PCSK9 and the results from recent phase II trials.     

Monoclonal Antibodies for Lipid Management

In recent years, biochemical and genetic studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a major mediator of low-density lipoprotein cholesterol (LDL-c) levels and thereby a potential novel target for reducing risk of coronary heart disease (CHD). These observations led to the development of PCSK9 inhibitors, which lower LDL-c levels more than any other non-invasive lipid-lowering therapy presently available. The PCSK9 inhibitors furthest along in clinical trials are subcutaneously injected monoclonal antibodies. These PCSK9 inhibitors have demonstrated LDL-c-lowering efficacy with acceptable safety in phase III clinical trials and may offer a useful therapy in addition to maximally tolerated HMG-CoA reductase inhibitors (statins) in certain patient groups. Longer-term data are required to ensure sustained efficacy and safety of this new class of medications. This review provides an overview of the biology, genetics, development, and clinical trials of monoclonal antibodies designed to inhibit PCSK9.