PCSK9抑制剂对动脉粥样硬化性脑梗死患者血脂水平影响的临床研究

目的 观察前蛋白转化酶枯草溶菌素9 (PCSK9)抑制剂对动脉粥样硬化性脑梗死（ASCI）患者血脂水平及预后的影响。方法 将2021年1月至2021年12月于湖北孝感市中心医院收治的100例符合纳入标准的ASCI患者随机分为对照组和试验组,每组各50例。对照组予以阿托伐他汀钙片治疗,试验组予以阿托伐他汀钙片+PCSK9抑制剂（瑞百安）治疗,药物干预周期为6个月。比较两组受试者用药前后血清PCSK9浓度、血脂水平、同型半胱氨酸（Hcy）及颈动脉内中膜厚度（IMT）等卒中危险因素,分析血清PCSK9水平与ASCI常见危险因素的相关性。结果 PCSK9抑制剂在阿托伐他汀钙片治疗的基础上可以显著降低ASCI患者血清PCSK9水平和血清低密度脂蛋白胆固醇（LDL-C）水平（P<0.05）;与对照组相比,试验组IMT显著降低（P<0.05）;试验组血清PCSK9水平与血清LDL-C显著相关。结论 PCSK9抑制剂作为新型降脂药物在阿托伐他汀钙片治疗的基础上可以降低受试者的LDL-C水平,改善患者的预后,降低动脉硬化性脑梗死的发生率。     

降胆固醇药物新靶标前蛋白转化酶枯草溶菌素9的研究进展

他汀类药物主要用于降低血低密度脂蛋白胆固醇(LDL-C)以及预防心血管疾病,但其临床疗效和机体的耐受性尚存在不稳定性.人类前蛋白转化酶枯草溶菌素9(PCSK9)属于前蛋白转化酶家族,主要由肝脏产生并分泌人血,可促进肝脏中低密度脂蛋白受体(LDLR)的降解,从而参与调控血LDL-C水平.人群中PCSK9的功能获得型或缺失型基因突变与血LDL-C含量、心血管疾病患病率密切相关.可通过负反馈机制上调PCSK9,促进LDLR的降解,从而降低他汀类药物的疗效.因此,抑制PCSK9活性可望成为治疗高胆固醇血症的一种新的有效方法.本文主要综述PCSK9调节胆固醇代谢及其临床应用的研究进展.     

PCSK9单克隆抗体降脂治疗新进展

高胆固醇血症是冠状动脉粥样硬化性疾病的重要危险因素之一,血脂控制良好可降低心血管疾病患者心血管事件的发生风险。他汀类药物是降脂治疗的基石,但仍有降脂效果未达标的情况发生,并可导致多种不良反应。前蛋白转化酶枯草溶菌素9(PCSK9)单克隆抗体是新型降脂药物。家族性高脂血症或心血管疾病患者在应用他汀类药物的基础上,联合PCSK9单克隆抗体可进一步降低低密度脂蛋白胆固醇水平,减少并发症发生。目前Evolocumab和Alirocumab两种PCSK9单克隆抗体已被批准应用于临床。     

PCSK9在脂代谢调节中作用的研究进展

血清中低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)浓度与冠心病的发生密切相关,而LDL-C主要是通过肝细胞表面的LDL受体(LDL receptor,LDLR)清除。前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin kexin type 9,PCSK9)可结合肝细胞表面LDLR并与其共同内吞入内体,介导LDLR进入溶酶体使其降解,从而参与血胆固醇的调节,在维持脂代谢稳态中发挥重要作用。目前对PCSK9的研究已取得一定的进展,但其发挥作用的确切机制还不是很清楚,在本文中作者就PCSK9在脂代谢调节中的作用以及其发挥作用的分子机制作一综述。     

PCSK9与动脉粥样硬化的研究进展

动脉粥样硬化是一种累及动脉壁的炎症性疾病,其主要特征是脂质和炎症细胞在大动脉内膜下聚积.前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂目前是临床上常用的降血脂药之一,虽然临床试验已证实PCSK9是降低血脂和预防及治疗动脉粥样硬化进展的生物靶点,但其生理作用尚未被完全阐明.目前多项证据表明,PCSK9可以通过调控脂蛋白代谢...     

PCSK9抑制剂与心血管事件关系的研究进展

动脉粥样硬化性心血管疾病(ASCVD)已成为全球居民死亡的主要原因.人体血脂紊乱,特别是低密度脂蛋白胆固醇(LDL-C)的增加,是影响动脉粥样硬化(AS)发生发展的最重要因素.前蛋白转化酶枯草溶菌素9(PCSK9)通过与低密度脂蛋白受体(LDLR)的结合,减少LDLR对血清LDL-C的清除.PCSK9抑制剂,如Alir...     

体检人群血清PCSK9与代谢综合征的相关性分析

目的：探讨体检人群中前蛋白转化酶枯草溶菌素9（proprotein convertase subtilisin/kexin 9,PCSK9）水平与代谢综合征（metabolism syndrome,MS）及其影响因素的相关性。方法：以南京医科大学第一附属医院1 442例体检人群为研究对象进行横断面研究,对入选者进行问卷调查、体格检查及代谢相关指标测定,用酶联免疫吸附实验（enzyme linked immunosorbent assay,ELISA）方法检测血清样本PCSK9水平,并统计分析PCSK9水平与代谢综合征及其组分的相关性。结果：代谢综合征组的年龄、男性比例、体重指数（body mass index,BMI）、收缩压（systolic blood pressure,SBP）、舒张压（diastolic blood pressure,DBP）、空腹血糖（fasting blood glucose,FBG）、甘油三酯（triglyceride,TG）、总胆固醇（total cholesterol,TC）、低密度脂蛋白胆固醇（low?density lipoprotein cholesterol,LDL?C）、尿酸（uric acid,UA）、PCSK9明显高于健康对照组,高密度脂蛋白胆固醇（high?density lipoprotein cholesterol,HDL?C）明显低于健康对照组（P < 0.05）。随着MS异常组分数目的增加,血清PCSK9水平逐渐升高（P趋势<0.05）。多因素Logistic回归分析结果显示,年龄、BMI、SBP、FBG、TG、TC、LDL?C、HDL?C是MS的危险因素,PCSK9与MS无明显相关性。结论：PCSK9与MS及多种代谢指标存在相关性,但受多种混杂因素影响,并不能证实PCSK9是MS的独立危险因子。     

家族性高胆固醇血症致病基因PCSK9的研究进展

家族性高胆固醇血症(FH)是一种常染色体单基因显性遗传性疾病,其主要的临床特征为血浆低密度脂蛋白胆固醇(LDL-C)水平明显升高、肌腱或皮肤黄色瘤、早发冠状动脉粥样硬化和冠状动脉粥样硬化性心脏病等。人类枯草溶菌素转化酶9(PCSK9)基因是FH的致病基因之一。PCSK9通过调节低密度脂蛋白受体在肝脏降解,从而间接调节LDL-C水平。PCSK9基因突变可分为失功能性突变和功能获得性突变,是目前降脂药物的研究热点。     

SREBP/PCSK9通路与抗精神病药物所致脂代谢紊乱相关性的研究进展

抗精神病药物是治疗精神分裂症的主要药物,但其使用会导致脂代谢紊乱,从而增加患者发生心血管疾病的风险,缩短患者的预期寿命,并严重影响治疗的依从性。目前,抗精神病药物引起脂代谢紊乱的具体机制尚不清楚。固醇调节元件结合蛋白(sterol regulatory element binding protein,SREBP)是调控脂代谢的关键转录因子。前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)作为SREBP下游调控基因之一,对低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)具有重要的调控作用,是最近降脂药物研究的重要靶点。近期研究表明,抗精神病药物可以通过SREBP/PCSK9通路影响脂代谢。深入了解该通路在抗精神药物相关代谢异常中的作用机制将促进精神分裂症患者脂代谢紊乱的预防和新药的研发应用。     

冠心病患者PCSK9基因D320N位点多态性及其临床意义

目的 探讨冠心病患者外周血人枯草溶菌素转化酶9(PCSK9)基因D320N多态性与冠心病的关系。方法 选取2014年1月至2016年1月在河北省人民医院就诊的不同类型（心绞痛、心肌梗死、无症状性心肌缺血、缺血性心肌病、猝死）冠心病患者3 450例为病例组;以同期健康体检人群1 100例为对照组。检测各组研究对象的血清血脂水平及PCSK9浓度。应用PCR结合DNA直接测序技术对各组PCSK9基因D320N（A/G）多态位点进行分型。采用多因素logistic回归分析PCSK9基因D320N多态位点与不同类型冠心病的关系。结果 病例组患者血清PCSK9浓度,TC、TG、LDL-C水平和、冠心病家族史和吸烟比例均高于对照组（t=108.267、52.8264、5.482、101.952,χ2=188.950、70.742;P<0.0015）,HDL-C水平低于对照组（t=-42.454,P<0.0015）;。病例组中猝死组各指标变化最大,无症状心肌缺血组变化最小 。病例组中AA、GA的基因型频率分别为3.6%、13.9%,高于对照组的1.1%、7.0%（χ2=36.60,17.74;P<0.001）;病例组中A等位基因的频率为0.105,高于对照组的0.046（χ2=70.4851,P<0.001）。病例组中猝死组AA、GA的基因型频率和A等位基因频率最高,无症状心肌缺血组最低（χ2=20.502、39.646,P<0.0501）。Logisticlogistic回归分析发现PCSK9基因D320N（A/G）多态位点AA基因型与冠心病的严重程度有关(OR值为7.964,95%CI为3.219~16.286,P<0.001=0.000) 。结论 PCSK9基因D320N（A/G）位点基因突变与冠心病有关,其中AA基因型可能是冠心病发生的独立危险因素。     

Effects of Hedan Tablet(荷丹片)on Lipid Profile,Proprotein Convertase Subtilisin/Kexin Type 9 and High-Density Lipoprotein Subfractions in Patients with Hyperlipidemia:A Primary Study

Objective: To investigate the effects of Hedan Tablet(荷丹片) on serum lipid profile, proprotein convertase subtilisin/kexin type 9(PSCK9) and high-density lipoprotein(HDL) subfractions in patients with hyperlipidemia. Methods: Thirty-seven patients with hyperlipidemia were randomized to treatment with Hedan Tablet 4.38 g/day as Hedan group(18 cases) or placebo(19 cases) as control group for 8 weeks. The lipid profile, PCSK9 and HDL subfractions were determined at day 0 and week 8 in both groups respectively. Results: Hedan treatment for 8 weeks mildly decreased serum low-density lipoprotein cholesterol(LDL-C) levels, while no changes were found in total cholesterol(TC), triglycerides(TG) and PCSK9 concentrations. Furthermore, Hedan treatment increased the concentration of large high-density lipoprotein cholesterol(HDL-C) and the percentage of large HDL subfraction, while decreased the concentration of small HDL-C and the percentage of small HDL subfraction without changing serum HDL-C levels in patients with hyperlipidemia. Conclusion: Hedan treatment of 4.38 g per day for 8 weeks could confer a favorable effects on serum LDL-C concentration as well as HDL subfractions.     

肥胖患者糖脂代谢特点及与前蛋白转化酶枯草溶菌素9关系的研究

目的:探讨青少年及年轻成人肥胖患者糖脂代谢的特点及与前蛋白转化酶枯草溶菌素9(PCSK9)的关系?方法:收集就诊患者54例(其中男22例,女32例),排除既往有糖尿病史者,对其进行问卷调查?体格检查以及相关代谢指标的测定,同时行口服葡萄糖耐量试验(OGTT)?用ELISA方法检测血清样本中PCSK9的水平?结果:体质指数(BMI)与空腹血糖(FBG)?空腹胰岛素(FINS)?空腹C肽(FCP)?胰岛素抵抗指数(HOMA-IR)呈正相关(r值分别为0.386?0.488?0.363?0.546,P均 < 0.05),与甘油三酯(TG)?总胆固醇(TC)?低密度脂蛋白胆固醇(LDL-C)呈正相关(r值分别为0.365?0.274?0.305,P均 < 0.05),与高密度脂蛋白胆固醇(HDL-C)呈负相关(r = -0.270,P < 0.05),BMI与C反应蛋白(CRP)?γ谷氨酰胺转肽酶(γGGT)呈正相关(r值分别为0.577?0.417,P均 < 0.05),与总胆红素(TBIL)呈负相关(r = -0.322,P < 0.05)?PCSK9水平与BMI?FINS?HOMA-IR呈正相关(r值分别为0.406?0.535?0.496,P均 < 0.05),但与TG?TC?LDL-C?HDL-C相关性不明显(r值分别为0.089?0.237?0.269?-0.002,P均 > 0.05)?CRP与FINS?FCP?HOMA-IR?TG呈正相关(r值分别为0.331?0.464?0.494?0.530,P均 < 0.05)?γGGT与FBG?TG呈正相关(r值分别为0.284?0.501,P均 < 0.05),与HDL-C呈负相关(r = -0.289,P < 0.05)?TBIL与FINS?FCP?LDL-C呈负相关(r值分别为-0.324?-0.290?-0.315,P均 < 0.05)?结论:肥胖青少年及年轻成人机体存在多种糖脂代谢指标的异常, 其中PCSK9与FINS和HOMA-IR密切相关?对青少年及年轻成人肥胖的预防有助于预防未来心血管疾病和2型糖尿病的发生?     

黄连解毒汤对高脂血症大鼠血脂代谢及其相关基因表达的影响

目的：观察黄连解毒汤对高脂血症大鼠血脂代谢及其相关基因表达的影响。方法：将50只SD大鼠随机分为正常对照组、模型组、立普妥（阿托伐他汀）组和低、高剂量黄连解毒汤组。除正常对照组外,其他组大鼠喂饲高脂饲料建立高脂血症大鼠模型。连续给药8周后,检测血清总胆固醇（total cholesterol,TC）、三酰甘油（triacylglycerol,TAG）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol,LDL-C）和高密度脂蛋白胆固醇（high—density lipoprotein cholesterol,HDL—C）水平,并检测各组大鼠肝脏脂蛋白脂酶（lipoprotein lipase,LPL）和肝脂酶（hepatic lipase,HL）活性;利用逆转录聚合酶链反应技术检测各组大鼠肝脏组织低密度脂蛋白受体（low—density lipoprotein receptor,LDLR）和过氧化物体增殖物活化受体γ（peroxisome proliferator—activated receptor γ,PPAR γ）mRNA的表达水平。结果：与正常对照组比较,模型组大鼠血清TC、TAG和LDL—C水平显著升高．HDL-C水平显著降低;肝脏LPL、HL活性和LDLR、PPARγmRNA表达水平明显下降。黄连解毒汤组血脂水平均较模型组有不同程度的改善,肝脏LPL、HL活性和LDLR、PPARγ mRNA表达水平明显升高。结论：黄连解毒汤可能是通过提高肝脏脂代谢酶的活性,促进肝脏LDI。R和PPARγmRNA的表达来调节脂质代谢紊乱的。     

阻塞性睡眠呼吸暂停低通气综合征患者血清前蛋白转化酶枯草溶菌素-9及低密度脂蛋白胆固醇水平变化及其对脑梗塞的预测作用

目的 :检测阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者血清前蛋白转化酶枯草溶菌素-9(PCSK9)及低密度脂蛋白胆固醇(LDL-C)水平变化及其对OSAHS并发脑梗死的预测作用。方法:从本院2010年以来门诊及住院患者中随机抽取OSAHS合并脑梗死患者27例(A组),单纯性OSAHS患者30例(B组)以及健康体检者30例(C组),用ELISA法检测3组患者血清中PCSK9的水平,全自动分析仪检测LDL-C水平。比较3组患者血清PCSK9及LDL-C水平变化,同时比较A、B两组患者睡眠呼吸监测指标,并对其血清PCSK9及LDL-C与睡眠呼吸监测指标进行直线相关分析。结果:1A组患者血清PCSK9、LDL-C水平高于B、C组(P<0.05);2睡眠呼吸监测指标显示,A组患者病情较B组严重(P<0.05);3A、B两组患者血清PCSK9、LDL-C水平分别与其睡眠呼吸暂停低通气指数(AHI)、睡眠呼吸障碍事件占总睡眠时间百分比、血氧饱和度<90%时间占总睡眠时间百分比呈正相关(P<0.05);与最低血氧饱和度及平均最低血氧饱和度呈负相关(P<0.05)。结论:OSAHS患者血清PCSK9及LDL-C升高幅度与其严重程度密切相关,并可作为OSAHS合并脑梗死的预测指标。     

Effect of Quercetin on Atherosclerosis Based on Expressions of ABCA1, LXR-α and PCSK9 in ApoE-/- Mice

Objective: To investigate the effect of quercetin on ATP binding cassette transporter A1(ABCA1), liver X receptor(LXR), and proprotein convertase subtilisin/kexin type 9(PCSK9) expressions in apo E-knockout(Apo E~(-/-) ) mice. Methods: The high-fat diet-induced atherosclerosis(AS) in Apo E~(-/-) mice was established. Thirtysix mice were divided into 3 groups using random number table method: model group(n=12), quercetin group(n=12), and atorvastatin group(n=12), with C57 BL/6 J mice of the same strain and age as the control group(n=12). Quercetin group and atorvastatin group were administrated with quercetin and atorvastatin by oral gavage, with doses of 12.5 and 4 mg/(kg·d), respectively. Animals in the control and model groups were given an equal volume of distilled water by oral gavage once per day for a total of 12 weeks. Western blot and immunohistochemical methods were employed to determine the aortic ABCA1, LXR-α and PCSK9 protein expression. Enzyme linked immunosorbent assay method was used to detect the expression of serum total cholesterol(TC), triglyceride(TG), high density lipoprotein-cholesterol(HDL-C), low density lipoproteincholesterol(LDL-C), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and IL-10, combined with tissue pathological examination. Results: Apo E~(-/-) mice fed with a high-fat diet had notable atherosclerosis lesions, with reduced ABCA1, LXR-α and IL-10 levels(all P0.01), elevated PCSK9, TNF-α and IL-6 expression, and increased TC and LDL-C contents(all P0.01). After quercetin intervention, the areas of AS plaques and the expressions of PCSK9, TNF-α and IL-6 were significantly reduced(all P0.01), while the expressions of ABCA1 and LXR-α were increased significantly(all P0.01). Conclusion: Quercetin effectively interfered with AS development by regulating the expressions of ABCA1, LXR-α and PCSK9 in Apo E~(-/-) mice.     

A novel mutation in proprotein convertase subtilisin/kexin type 9 gene leads to familial hypercholesterolemia in a Chinese family

Background Familial hypercholesterolemia （FH） is an autosomal disorder associated with elevated plasma low density lipoprotein （LDL） levels leading to premature coronary heart disease （CHD）. As a result of long-term hyperlipemia, FH patients will present endarterium thickening and atherosclerosis. In the present study we scanned the related gene of a clinically diagnosed autosomal genetic hypercholesterolemia family for the possible mutations and established eukaryotic expression vector of mutation of proprotein convertase subtilisin/kexin type 9 （PCSK9） gene with gene recombination technique to investigate the contributions of the variation on low density lipoprotein receptor （LDL-R） metabolism and function alternation.Methods Mutation detection was conducted for LDL-R, apolipoprotein B100 （apoB100） and PCSK9 gene with nucleotide sequencing in a Chinese FH family. The full-length cDNA of wild type PCSK9 gene （WT-PCSK9） was obtained from Bel-7402. Site mutagenesis was used to establish the recombinant eukaryotic expression vector carrying pathogenic type of PCSK9 gene and the inserted fragment was sequenced. With the blank vector as control, liposome transfection method was used to transfect the Bel-7402 cells with recombinant plasmid. The expression of LDL-R mRNA was examined by RT-PCR. PCSK9 and the expression of LDL-R protein were determined by Western blotting. Results The G→T mutation at the 918 nucleotide of PCSK9 gene resulted in the substitution of the arginine by a serine at the codon 306 of exon 6. After sequencing, it was confirmed that the inserted fragment of established expression vector had correct size and sequence and the mutant was highly expressed in Bel-7402 cells. There was no significant variation in the levels of LDL-R mRNA. LDL-R mature protein was decreased by 57% after the cells were transfected by WT-PCSK9 plasmid. Mature LDL-R was significantly decreased by 12% after the cells were transfected by R306S mutant as evidenced by gray scale scanning, suggesting that the new mutant R306S can significantly decrease the expression of mature LDL-R protein.Conclusions A novel missense mutation of PCSK9 gene, R306S, was found and the eukaryotic expression vectors of mutant and wild-type of PCSK9 gene were established. There was no significant variation in the levels of LDL-R mRNA. The R306S mutation could significantly lead to the decrease of LDL-R mature protein expression, which might be the pathogenic gene of the FH family.     

2型糖尿病患者血清PCSK9与动脉粥样硬化指标的相关性分析

目的:研究2型糖尿病(type 2 diabetes mellitus,T2DM)患者血清前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin 9,PCSK9)与动脉粥样硬化(atherosclerosis,AS)指标的相关性?方法:对351例T2DM患者进行病史采集?颈部及下肢血管彩色多普勒检查,测定其PCSK9水平?结果:T2DM合并AS组患者的血清PCSK9水平高于T2DM无AS组(P < 0.05),血清PCSK9水平与T2DM患者的颈总动脉内中膜厚度(carotid artery intima-media thickness,CIMT)呈正相关(P < 0.01),与右侧颈总动脉(RCCA)内径?RCCA峰值/次峰值(PI)?右侧颈内动脉(RICA)PI?左侧颈总动脉(LCCA)PI?左侧颈内动脉(LICA) PI?RICA 阻力指数(RI)?LCCA RI等颈动脉粥样硬化相关性指标呈正相关(P < 0.05),而与RCCAVmax?RCCA Vmin?RCCA Tamx等指标呈负相关(P < 0.05)?结论:T2DM患者血清PCSK9水平与评估AS程度的指标密切相关,可能成为临床预测及评估T2DM患者AS相关大血管疾病发生风险的指标?     

狼疮早发急性心肌梗死患者PCSK9水平与临床指标的关联性分析

目的:检测育龄女性系统性红斑狼疮(systemic lupus erythematosus,SLE)并急性心肌梗死(acute myocardial infarction,AMI)患者治疗前后血清PCSK9水平,并分析其与临床指标的相关性.方法:纳入30例育龄女性SLE合并AMI患者(SLE心梗组),30名年龄匹配、未...