天然化合物抑制前蛋白转化酶枯草溶菌素9的作用机制研究进展

Research progress on the mechanism of natural compounds inhibitingproprotein convertase subtilisin/kexin type 9

动脉粥样硬化(atherosclerosis, AS)是一种复杂的慢性进行性动脉疾病,被视为全球死亡的重要原因。高水平的血浆低密度脂蛋白胆固醇(low density lipoprotein-cholesterol, LDL-C)是AS发生和发展的关键危险因素。血浆中循环的前蛋白转化酶枯草溶菌素9 (proprotein convertase subtilisin/kexin type 9, PCSK9)是一种肝细胞合成的丝氨酸蛋白酶,是低密度脂蛋白受体(low density lipoprotein receptor,LDLR)的关键调节因子,在控制血浆LDL-C水平方面发挥着关键作用,它通过与肝脏LDLR结合,形成PCSK9-LDLR复合物导致LDLR在溶酶体中降解,并减少肝细胞膜表面的LDLR的数量,进而导致血浆LDL-C水平升高。目前,临床常用他汀类降脂药物,如阿托伐他汀调节LDL-C水平,延缓AS,但药物起效慢,单一应用难以达到理想的效果,且会在不同程度上产生不良影响。因此, PCSK9是一种新的降低胆固醇的治疗靶点。本综述旨在阐明调控PCSK9的途径及改善AS的天然化合物的研究现状和潜在的治疗意义,以期为防治AS提供参考。

Atherosclerosis(AS)is a complex chronic progressive arterial disease,which is regarded as an important cause of death worldwide.High levels of plasma low density lipoprotein-cholesterol(LDL-C)are key risk factors for the occurrence and development of atherosclerosis.Proprotein convertase subtilisin/kexin type 9(PCSK9)circulating in plasma is a serine protease synthesized by liver cells,which is a key regulator of low density lipoprotein receptor(LDLR)and plays a crucial role in controlling plasma LDL-C levels.It binds to liver LDLR to form the PCSK9-LDLR complex,which leads to degradation of LDLR in lysosomes,and reduce the amount of LDLR on the surface of liver cell membrane,which in turn leads to elevated plasma LDL-C levels.At present,statin based lipid-lowering drugs are commonly used in clinical practice,such as atorvastatin,which regulates LDL-C levels and delays AS,but the drug takes effect slowly,and single use is difficult to achieve the desired effect,and can have adverse effects to varying degrees.Therefore,PCSK9 is a new therapeutic target for lowering cholesterol.This review aimedto elucidated the research status and potential therapeutic significance of natural compounds that regulate PCSK9 and improve AS,in order to provide reference for the prevention and treatment of AS.