前蛋白转化酶枯草溶菌素9抑制剂的研究进展

前蛋白转化酶枯草溶菌素9(PCSK9)是一种主要在肝细胞中表达的分泌型丝氨酸蛋白酶。PCSK9能够与低密度脂蛋白受体(LDLR)结合形成复合物,并通过溶酶体途径使LDLR降解,从而减少细胞表面LDLR的数量,最终导致血浆低密度脂蛋白胆固醇(LDLC)水平升高。近年来,PCSK9抑制剂成为一个治疗高胆固醇血症及动脉粥样硬化性心血管疾病(ASCVD)药物研发的新热点。目前全球上市了三款PCSK9抑制剂,包括依洛尤单抗(Evolocumab)、阿利珠单抗(Alirocumab)及小干扰RNA药物Inclisiran(Leqvio~?)。本文对PCSK9的结构、功能、抑制剂的研究进展进行了综述。     

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.     

Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia

Background and aimsTwo recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL.Methods and resultsMarkers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001).ConclusionsThe present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.     

ABO血型与血脂和PCSK9相关性研究

背景和目的：前蛋白转化酶枯草杆菌蛋白酶9(Proprotein convertase subtilisin/kexin type 9 ,PCSK9),是一个近期发现的在胆固醇平衡、高脂血症和冠心病治疗中起重要作用的新成员。但是决定PCSK9水平的因素尚不明确。已知ABO血型与胆固醇代谢相关。因此,本研究探讨了ABO血型和PCSK9水平之间的联系。     

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。     

新型降胆固醇药物前蛋白转化酶枯草溶菌素9抑制剂的研究进展

动脉粥样硬化性心血管疾病已成为我国居民主要死亡原因之一,血脂异常是动脉粥样硬化发生、发展的重要因素。前蛋白转化酶枯草溶菌素9(PCSK9)是肝脏合成的分泌型丝氨酸蛋白酶,与低密度脂蛋白受体结合使其降解,减少低密度脂蛋白受体对血清低密度脂蛋白胆固醇的清除。而通过抑制PCSK9,可阻止低密度脂蛋白受体降解,促进低密度脂蛋白胆固醇的清除。近年来,以PCSK9抑制剂为代表的新型药物受到越来越多的关注,取得令人瞩目的进展。本文对PCSK9抑制剂的研究新进展进行综述。     

Clinical guidance on the contemporary use of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies

There is now significant evidence for the benefits of lowering low-density lipoprotein cholesterol (LDL-c) to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Although statins are the most widely prescribed lipid-lowering therapy that effectively lower LDL-c, especially in combination with ezetimibe, some patients require adjunctive therapy to further lower LDL-c and mitigate attendant risk of ASCVD. The gap can be filled by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies whose use is currently supported by two recent cardiovascular outcome studies and new treatment guidelines. We provide an overview of extant studies investigating PCSK9 monoclonal antibodies in various patient populations, an update of the guidelines regarding their use and a case-based discussion.     

From the Cover: A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the LDL receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to an epitope on PCSK9 adjacent to the region required for LDLR interaction. In vitro, mAb1 inhibits PCSK9 binding to the LDLR and attenuates PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake. A combination of mAb1 with a statin increases LDLR levels in HepG2 cells more than either treatment alone. In wild-type mice, mAb1 increases hepatic LDLR protein levels ≈2-fold and lowers total serum cholesterol by up to 36%: this effect is not observed in LDLR^−/− mice. In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia.     

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。     

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

Diabetic dyslipidaemia, characterized by quantitative, qualitative and kinetic changes in all major circulating lipids, contributes to the increased cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). A promising therapeutic avenue is the inhibition of the proprotein convertase subtilisin kexin 9 (PCSK9) with human monoclonal antibodies (mAbs) that potently reduce plasma low-density lipoprotein cholesterol (LDL-C) levels on top of statin treatment. The aim of this review is to evaluate the efficacy of PCSK9 inhibitors to lower the residual cardiovascular risk of T2DM patients and to discuss the safety of PCSK9 inhibition in these patients. PCSK9 inhibitors potently lower plasma LDL-C levels in T2DM patients and reduce risk for the development of cardiovascular disease. Anti-PCSK9 mAbs are generally not more or less effective in T2DM patients compared to a general high-risk population. Nevertheless, due to their higher cardiovascular risk, the absolute risk reduction of major cardiovascular events is more significant in T2DM patients. This suggests that treatment of T2DM patients with anti-PCSK9 mAbs could be attractive from a cost-effectiveness perspective. Treatment with anti-PCSK9 mAbs did not result in significant treatment-emergent adverse effects. While genetic studies suggest a potential link between PCSK9 inhibition and glucose homeostasis, anti-PCSK9 mAbs did not worsen glycaemic control in T2DM patients, but their safety should be verified after a longer-term follow-up.     

枯草溶菌素转换酶9与血脂代谢调节

高胆固醇血症及其引起的冠心病已成为威胁人类健康的最重要因素,血脂代谢相关研究日益受到重视.最近的研究表明,一种前蛋白转换酶家族成员--枯草溶菌素转换酶9(proproteinconvertasc kexin type 9,PCSK9)在血脂代谢调节中起着重要作用.PCSK9基因的表达和突变与低密度脂蛋白受体(low-density lipoprotein receptor,LDLR)含量密切相火,PCSK9高度表达能促进LDLR降解,从而提高血浆LDL水平;反之,PCSK9基因抑制则引起血浆LDL水平降低.因此,通过研究PCSK9的作用机制,有望开发出治疗高胆固醇血症、控制高血脂和预防冠心病的新型药物.     

冠心病患者体内前蛋白转化酶枯草溶菌素9水平与炎性因子的相关性分析

目的:探讨冠状动脉粥样硬化性心脏病(CAD)患者血浆前蛋白转化酶枯草溶菌素9(PCSK9)与血脂各指标及性因子的相关性。方法:入选210例未行降脂治疗的胸痛患者,入院后根据冠状动脉造影检查结果分为冠心病组120例和对照组(非冠心病)90例。收集临床资料,采集空腹静脉血检测血常规、血生化等各项指标。采用酶联免疫吸附实验(ELISA)检测患者血浆PCSK9、白介素10(IL-10)水平。结果:两组资料对比,CAD组吸烟及糖尿病史的比例高于对照组,空腹血糖、LDL-C、IL-10、PCSK9水平明显高于对照组,HDL-C水平低于对照组,差异有统计学意义。Logistic回归分析显示在调整了性别、高血压、TG、TC、载脂蛋白A1(Apo A1)、Apo B因素后,老年、吸烟、糖尿病史、LDL-C、脂蛋白(a)、HDL、PCSK9是CAD的独立危险因素。PCSK9与LDL-C、Apo B水平呈正相关;与炎性标志物hs-CRP、中性粒细胞和IL-10呈正相关。结论:PCSK9是CAD的独立危险因素,与动脉粥样硬化(As)的形成和发展有密切关系。PCSK9水平与抗炎细胞因子IL-10及hs-CRP正相关,提示IL-10和hs-CRP与PCSK9共同参与了AS的形成和发展。     

急性心肌梗死治疗中应用前蛋白转化酶枯草杆菌蛋白酶/kexin9型抑制剂对对比剂所致急性肾损伤的影响

目的 探讨前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9)抑制剂在急性心肌梗死患者行经皮冠状动脉介入(PCI)治疗过程中对对比剂所致急性肾损伤(CI-AKI)的作用。方法 回顾性分析行PCI手术的急性心肌梗死患者235例,并于术后24～72 h内复查血肌酐。按照有无应用PCSK9抑制剂依洛尤单抗进行分组,比较相关指标;按照有无发生CI-AKI进行分组,对数据进行单因素分析,筛选出导致CI-AKI发生的可疑影响因素,然后纳入可疑影响因素及业界公认的影响因素进行多因素logistic回归分析。结果 按照有无应用依洛尤单抗分组,与对照组比较,依洛尤单抗组CI-AKI发病率降低(7.8%比20.0%,χ²=7.21,P<0.01)。多因素logistic回归分析发现应用依洛尤单抗是CI-AKI发生的保护因素(OR=0.28,95%CI 0.11～0.71,P<0.01)。结论 急性心肌梗死患者行PCI治疗中应用PCSK9抑制剂可降低CI-AKI的发生率。