摘要
脂蛋白(a)(lipoprotein(a),Lp(a))在结构上与低密度脂蛋白相似,是动脉粥样硬化性心血管疾病发病的独立危险因素和潜在的治疗靶点.前蛋白转换酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)抑制剂可有效降低Lp(a)的循环水平并减少心血管事件风险.本文综合近年来的相关研究,阐述PCSK9抑制剂减少Lp(a)合成和促进其降解的相关机制,分析该领域所面临的挑战和未来的发展方向.
Abstract
Lipoprotein(a)(Lp(a))is a complex circulating lipoprotein,and increasing evidence has demonstrated its role as a risk factor for atherosclerotic cardiovascular disease and as a possible therapeutic target.Proprotein converting enzyme proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitor significantly decreases the circulating level of Lp(a)and reduces the risk of cardiovascular events.Based on the research results in recent years,this review will systematically summarize the relevant mechanisms of PCSK9 inhibitor reducing Lp(a)synthesis and promoting its degradation.The mechanisms are influenced by whether statins used in combination and baseline levels of Lp(a).PCSK9 inhibitors decrease Lp(a)levels mainly by reducing Lp(a)synthesis.However,the importance of low-density lipoprotein receptor(LDLR)mediated enhancing Lp(a)degradation gradually increases when the LDL level decreases.Meanwhile,many other receptor pathways may also exist,including very low-density lipoprotein(VLDL)receptor,LDL receptor-related protein 1,CD36,toll-like receptor 2,scavenger receptor B1 and plasminogen receptor.At present,further studies are still needed to explore the mechanisms by which PCSK9 inhibitors reduce Lp(a)level,such as inhibition of Lp(a)synthesis and intracellular assembly,and LDLR-mediated Lp(a)degradation.In addition,whether the reduction of Lp(a)level by PCSK9 inhibitor is related to age,gender and race and whether the dose-effect relationship of reducing Lp(a)is influenced by background lipid level,all of which require in-depth exploration.In short,the cellular and molecular mechanisms underlying the regulation of Lp(a)synthesis and degradation is not completely clear.It is worth carrying out relevant research to provide a theoretical basis for better clinical application of such drugs.
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