Wiciński Michał, Żak Jarosław, Malinowski Bartosz, Popek Gabriela, Grześk Grzegorz
Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium, Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-090 Bydgoszcz, Poland.
EPMA J. 2017 Aug 14;8(4):391-402. doi: 10.1007/s13167-017-0106-6. eCollection 2017 Dec.
In the following review, authors described the structure and biochemical pathways of PCSK9, its involvement in LDL metabolism, as well as significances of proprotein convertase subtilisin/kexin type 9 targeted treatment. PCSK9 is a proprotein convertase, which plays a crucial role in LDL receptor metabolism. Transcription and translation of PCSK9 is controlled by different nuclear factors, such as, SREBP and HNF1α. This review focuses on interactions between PCSK9 and LDL receptor, VLDLR, ApoER2, CD36, CD81, and others. The role of PCSK9 in the inflammatory process is presented and its influence on cytokine profile (IL-1, IL-6, IL-10, TNF) in atherosclerotic plaque. Cholesterol metabolism converges also with diabetes by mTORC1 pathways. PCSK9 can be altered by oncologic pathways with utilization of kinases, such as Akt, JNK, and JAK/STAT. Finally, the article shows that blocking PCSK9 has proapoptotic capabilities. Administration of monoclonal antibodies against PCSK9 reduced mortality rate and cardiovascular events in randomized trials. On the other hand, immunogenicity of new drugs may play a crucial role in their efficiency. Bococizumab ended its career following SPIRE-1,2 outcome. PCSK9 inhibitors have enormous potential, which had been reflected by introducing them (as a new class of drugs reducing LDL concentration cholesterol) into New Lipid Guidelines from Rome 2016. Discoveries in drugs development are focused on blocking PCSK9 on different levels. For example, silencing messenger RNA (mRNA of PCSK9) is a new alternative against hypercholesterolemia. Peptides mimicking EGF-A domain of the LDL receptor are gaining significance and hopefully they will soon join others. The significance of PCSK9 has just been uncovered and further data is still required to understand their activity.
在以下综述中，作者描述了前蛋白转化酶枯草溶菌素9型（PCSK9）的结构和生化途径、其在低密度脂蛋白（LDL）代谢中的作用，以及PCSK9靶向治疗的意义。PCSK9是一种前蛋白转化酶，在LDL受体代谢中起关键作用。PCSK9的转录和翻译受不同核因子控制，如固醇调节元件结合蛋白（SREBP）和肝细胞核因子1α（HNF1α）。本综述重点关注PCSK9与LDL受体、极低密度脂蛋白受体（VLDLR）、载脂蛋白E受体2（ApoER2）、CD36、CD81等之间的相互作用。阐述了PCSK9在炎症过程中的作用及其对动脉粥样硬化斑块中细胞因子谱（白细胞介素-1、白细胞介素-6、白细胞介素-10、肿瘤坏死因子）的影响。胆固醇代谢还通过哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）途径与糖尿病相关。PCSK9可通过利用激酶（如蛋白激酶B（Akt）、应激活化蛋白激酶（JNK）和Janus激酶/信号转导及转录激活因子（JAK/STAT））的肿瘤学途径发生改变。最后，文章表明阻断PCSK9具有促凋亡能力。在随机试验中，给予抗PCSK9单克隆抗体可降低死亡率和心血管事件。另一方面，新药的免疫原性可能对其疗效起关键作用。在SPIRE-1、2试验结果公布后，bococizumab停止了研发。PCSK9抑制剂具有巨大潜力，这一点已在其被纳入2016年罗马新血脂指南（作为一类降低LDL胆固醇浓度的新药）中得到体现。药物研发的探索集中在不同水平阻断PCSK9。例如，沉默信使核糖核酸（PCSK9的mRNA）是治疗高胆固醇血症的一种新选择。模拟LDL受体表皮生长因子样A结构域（EGF-A）的肽正变得越来越重要，有望很快成为其他治疗手段。PCSK9的重要性刚刚被发现，仍需要更多数据来了解其活性。
