心血管疾病的重要靶点PCSK9及其抑制剂的研究进展

Research progress of PCSK9 and its inhibitors-an important target of cardiovascular diseases

高水平的低密度脂蛋白胆固醇(LDL-C)与心血管疾病风险相关。枯草溶菌素前蛋白转换酶9(PCSK9)由肝脏产生,在多个组织和细胞中表达。与肝细胞表面LDLR结合后形成PCSK9/LDLR复合物,导致LDLR被溶酶体降解。抑制PCSK9可减少LDLR降解,提高LDL-C在循环中的清除率,从而降低血液中胆固醇水平。此外,PCSK9还参与动脉粥样硬化、心衰和心肌梗死进程,并存在于各种类型的感染(细菌或病毒)和脓毒症中,与多种炎症标志物相关。鉴于其多种生理作用,抑制细胞外和细胞内PCSK9具有临床意义。目前临床应用的PCSK9抑制剂主要是单克隆抗体,但随着新类型抑制剂的研究,会有更多高效、经济的药物供临床医生选择,如反义寡核苷酸、RNA干扰药物、疫苗、小分子抑制剂等。

High level of low-density lipoprotein cholesterol(LDL-C)is related to the risk of cardiovascular disease.Proprotein convertase subtilisin/kexin type 9(PCSK9)is a kind of protein produced by liver and expressed in multiple tissues and cells.PCSK9 binds to LDLR on the surface of hepatocytes to form a PCSK9/LDLR complex,which degraded by lysosomes.Inhibition of PCSK9 can reduce the degradation of LDLR and increase the clearance rate of LDL-C in circulation,thus reducing the level of blood cholesterol.In addition,PCSK9 is involved in atherosclerosis,heart failure and myocardial infarction,and exists in various types of infections(bacteria or viruses)and sepsis,and is associated with a variety of inflammatory markers.In view of its various physiological effects,the inhibition of extracellular and intracellular PCSK-9 has clinical significance.At present,the main PCSK9 inhibitors used in clinic are monoclonal antibodies.However,with the development of new types of PCSK9 inhibitors,there will be more efficient and economical drugs for clinicians to choose,such as antisense oligodeoxynucleotides,RNA interference drugs,vaccines,small molecule inhibitors.