目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取202...目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取2023年1月-2024年12月在天津市胸科医院心内科就诊且应用英克司兰或PCSK9单抗治疗的ACS患者87例,依据其用药种类不同,将其分为英克司兰组(n=34)和PCSK9单抗组(n=34)。收集分析真实世界中ACS患者治疗前及治疗后d 30,d 90,d 180时的低密度脂蛋白(low density lipoprotein,LDL)降幅、达标率及血脂谱,以评估治疗获益。通过标准差(standard deviation,SD)、平均连续变异度(average successive variability,ASV)、变异系数(coefficient of variation,CV)和校正独立于均值的变异性(variation independent of mean,VIM)评估两组的血脂变异性差异。结果:治疗后30 d时,英克司兰组和PCSK9单抗组患者LDL-C降幅(P=0.126)和达标率(P=0.300)无显著性差异;治疗后90 d及180 d时,英克司兰组LDL-C降幅(P=0.048;P=0.038)及达标率(P=0.006;P=0.010)均显著优于PCSK9单抗组。此外,与PCSK9单抗组相比,英克司兰组的血脂变异性更小(SD:0.16 vs 0.37,P=0.01;CV:19.15 vs 33.24,P=0.02;ASV:0.19 vs 0.48,P=0.01;VIM:18.57 vs 33.98,P=0.05)。结论:对ACS患者予以英克司兰治疗可同时实现短期和长期持续的LDL-C降低效果,提高达标率,且安全性良好。展开更多
PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑...PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.展开更多
【目的】分析保山猪蛋白转化酶枯草素/酮蛋白4型(proprotein convertase subtilisin/kexin type 4,PCSK4)的分子特征、转录表达调控和蛋白功能。【方法】基于保山猪睾丸全转录组数据,通过生物信息学方法对PCSK4进行功能注释,并构建PCSK...【目的】分析保山猪蛋白转化酶枯草素/酮蛋白4型(proprotein convertase subtilisin/kexin type 4,PCSK4)的分子特征、转录表达调控和蛋白功能。【方法】基于保山猪睾丸全转录组数据,通过生物信息学方法对PCSK4进行功能注释,并构建PCSK4的长链非编码RNA和小RNA(miRNA)调控网络。【结果】PCSK4编码序列长2505 bp,编码834个氨基酸。蛋白质功能分析表明:PCSK4具有较多无规则卷曲和磷酸化位点。进化及邻近基因分析表明:PCSK4在进化过程中保守性较高。功能富集分析表明PCSK4与多个参与精子获能、受精、精卵识别的蛋白(如ACRBP、ACR、ADAM2等)存在互作关系,这些蛋白对应基因的表达量表明:PCSK4与MBTPS1、ACRBP、CDKN2A、DPY19L2显著相关。竞争性内源RNA调控网络分析表明5个miRNA可靶向调控PCSK4,功能注释显示其在生殖过程、蛋白质加工、受精等功能中发挥重要作用。【结论】本研究为进一步探讨PCSK4在保山猪精子发生过程,特别是受精与精子成熟阶段等重要生物学过程提供了基础资料。展开更多
蛋白转化酶subtilisin/keexin type-9 (PCSK9)是一种通过与肝脏LDL受体(LDLR)结合来调节低密度脂蛋白(LDL)胆固醇代谢的蛋白,最终导致其溶酶体降解和低密度脂蛋白胆固醇水平升高。治疗策略基于特异性抗体阻断PCSK9 (Alirocumab, Evolocu...蛋白转化酶subtilisin/keexin type-9 (PCSK9)是一种通过与肝脏LDL受体(LDLR)结合来调节低密度脂蛋白(LDL)胆固醇代谢的蛋白,最终导致其溶酶体降解和低密度脂蛋白胆固醇水平升高。治疗策略基于特异性抗体阻断PCSK9 (Alirocumab, Evolocumab)和小调节RNA (siRNA)阻断其产生(Inclisiran)。临床试验评价这些药物在降低动脉粥样硬化性心血管疾病患者血清低密度脂蛋白水平和改善预后方面具有很高的疗效。大多数研究都集中在PCSK9对LDLRs的作用以及随后低密度脂蛋白浓度的增加。越来越多的证据表明,PCSK9对心血管的不良影响,特别是其对血管壁的动脉粥样硬化作用,也可能是由独立于其对脂质代谢影响的机制引起的。PCSK9诱导促炎细胞因子的表达,促进血管壁炎症,促进心肌细胞凋亡、铁下沉和自噬,从而参与心血管疾病的发生和进展。文章对PCSK9的结构、作用以及相关疾病方面的研究进行了综述,以期为未来的研究提供一个可能的研究思路和方向。Protein convertase subtilisin/keexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and elevated LDL cholesterol levels. Treatment strategies are based on specific antibodies blocking PCSK9 (Alirocumab, Evolocumab) and small regulatory RNA (siRNA) blocking its production (Inclisiran). Clinical trials have evaluated the high efficacy of these drugs in reducing serum low-density lipoprotein levels and improving outcomes in patients with atherosclerotic cardiovascular disease. Most studies have focused on the effect of PCSK9 on LDLRs and the subsequent increase in LDL concentration. Accumulating evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vessel wall, may also be caused by mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines and promotes vascular wall inflammation, cardiomyocyte apoptosis, iron subsidence, and autophagy, thereby participating in the occurrence and progression of cardiovascular diseases. This article reviews the structure, function, and related diseases of PCSK9, in order to provide a possible research idea and direction for future research.展开更多
文摘目的:观察两类以前蛋白转化酶枯草溶菌素/kexin9型(PCSK9)为靶点的降脂治疗药物——小干扰RNA(small interfering RNA;siRNA)英克司兰与PCSK9单抗在我国急性冠状动脉综合征(acute coronary syndrome,ACS)患者中的疗效差异。方法:选取2023年1月-2024年12月在天津市胸科医院心内科就诊且应用英克司兰或PCSK9单抗治疗的ACS患者87例,依据其用药种类不同,将其分为英克司兰组(n=34)和PCSK9单抗组(n=34)。收集分析真实世界中ACS患者治疗前及治疗后d 30,d 90,d 180时的低密度脂蛋白(low density lipoprotein,LDL)降幅、达标率及血脂谱,以评估治疗获益。通过标准差(standard deviation,SD)、平均连续变异度(average successive variability,ASV)、变异系数(coefficient of variation,CV)和校正独立于均值的变异性(variation independent of mean,VIM)评估两组的血脂变异性差异。结果:治疗后30 d时,英克司兰组和PCSK9单抗组患者LDL-C降幅(P=0.126)和达标率(P=0.300)无显著性差异;治疗后90 d及180 d时,英克司兰组LDL-C降幅(P=0.048;P=0.038)及达标率(P=0.006;P=0.010)均显著优于PCSK9单抗组。此外,与PCSK9单抗组相比,英克司兰组的血脂变异性更小(SD:0.16 vs 0.37,P=0.01;CV:19.15 vs 33.24,P=0.02;ASV:0.19 vs 0.48,P=0.01;VIM:18.57 vs 33.98,P=0.05)。结论:对ACS患者予以英克司兰治疗可同时实现短期和长期持续的LDL-C降低效果,提高达标率,且安全性良好。
文摘PCSK9抑制剂通过靶向调控低密度脂蛋白受体(LDLR)降解,已成为动脉粥样硬化性心血管疾病(ASCVD)治疗的革命性策略。本文结合国内外研究进展,从以下三方面进行系统阐述:1) 分子机制:PCSK9通过催化结构域与LDLR结合,介导其溶酶体降解,而抑制剂可恢复LDLR再循环,降低LDL-C达60%~70%;2) 药物研发:单克隆抗体(Alirocumab、Evolocumab)显著降低MACE风险15%~20%,RNA干扰疗法(Inclisiran)实现半年一次给药,口服小分子(MK-0616)突破生物制剂限制;3) 多途径保护:除降脂外,PCSK9抑制剂通过抑制炎症(hs-CRP降低37%)、调节免疫(Treg/Th17平衡)及改善内皮功能(FMD提升12%)发挥协同效应。未来需聚焦长期安全性验证、成本效益优化及联合疗法开发,以全面提升ASCVD的防治水平。PCSK9 inhibitors have become a revolutionary strategy for the treatment of atherosclerotic cardiovascular disease (ASCVD) by targeting and regulating low-density lipoprotein receptor (LDLR) degradation. Based on the research progress at home and abroad, this paper systematically describes the following three aspects: 1) Molecular mechanism: PCSK9 binds to LDLR through catalytic domain, mediates lysosomal degradation, while inhibitors can restore LDLR recycling and reduce LDL-C by 60%~70%;2) Drug development: Monoclonal antibodies (Alirocumab, Evolocumab) significantly reduced the risk of MACE by 15%~20%, RNA interference therapy (Inclisiran) achieved semi-annual administration, and oral small molecules (MK0616) broke the limit of biologics;3) Multipathway protection: In addition to lipid-lowering, PCSK9 inhibitors play a synergistic role by inhibiting inflammation (37% reduction in hs-CRP), modulating immunity (Treg/Th17 balance), and improving endothelial function (12% increase in FMD). The future needs to focus on long-term safety validation, cost-effectiveness optimization, and combination therapy development to comprehensively improve the level of ASCVD prevention and treatment.
文摘蛋白转化酶subtilisin/keexin type-9 (PCSK9)是一种通过与肝脏LDL受体(LDLR)结合来调节低密度脂蛋白(LDL)胆固醇代谢的蛋白,最终导致其溶酶体降解和低密度脂蛋白胆固醇水平升高。治疗策略基于特异性抗体阻断PCSK9 (Alirocumab, Evolocumab)和小调节RNA (siRNA)阻断其产生(Inclisiran)。临床试验评价这些药物在降低动脉粥样硬化性心血管疾病患者血清低密度脂蛋白水平和改善预后方面具有很高的疗效。大多数研究都集中在PCSK9对LDLRs的作用以及随后低密度脂蛋白浓度的增加。越来越多的证据表明,PCSK9对心血管的不良影响,特别是其对血管壁的动脉粥样硬化作用,也可能是由独立于其对脂质代谢影响的机制引起的。PCSK9诱导促炎细胞因子的表达,促进血管壁炎症,促进心肌细胞凋亡、铁下沉和自噬,从而参与心血管疾病的发生和进展。文章对PCSK9的结构、作用以及相关疾病方面的研究进行了综述,以期为未来的研究提供一个可能的研究思路和方向。Protein convertase subtilisin/keexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and elevated LDL cholesterol levels. Treatment strategies are based on specific antibodies blocking PCSK9 (Alirocumab, Evolocumab) and small regulatory RNA (siRNA) blocking its production (Inclisiran). Clinical trials have evaluated the high efficacy of these drugs in reducing serum low-density lipoprotein levels and improving outcomes in patients with atherosclerotic cardiovascular disease. Most studies have focused on the effect of PCSK9 on LDLRs and the subsequent increase in LDL concentration. Accumulating evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vessel wall, may also be caused by mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines and promotes vascular wall inflammation, cardiomyocyte apoptosis, iron subsidence, and autophagy, thereby participating in the occurrence and progression of cardiovascular diseases. This article reviews the structure, function, and related diseases of PCSK9, in order to provide a possible research idea and direction for future research.
