PCSK9抑制剂对脑梗死的防治作用及治疗机理研究

Study on the Preventive and Therapeutic Effects of PCSK9 Inhibitor on Cerebral Infarction and Its Therapeutic Mechanism

摘要: 脑梗死(Cerebral Infarction, CI)作为全球范围内致死、致残的主要原因之一，其发病与低密度脂蛋白胆固醇(LDL-C)介导的动脉粥样硬化(AS)密切相关。前蛋白转化酶枯草溶菌素9型(PCSK9)抑制剂通过靶向抑制PCSK9与低密度脂蛋白受体(LDL-R)结合，显著降低LDL-C水平，成为防治CI的新型策略。本文综述了PCSK9抑制剂(PCSK9i)的作用机制及其在CI预防和治疗中的多效性。PCSK9i包括单克隆抗体(mAb)制剂如：阿利西尤单抗(alirocumab)和依洛尤单抗(evolocumab)，以及小干扰RNA制剂如英克司兰(inclisiran)，分别通过阻断PCSK9功能或抑制其合成，实现长效降脂。除降脂外，PCSK9i还可通过抑制炎症反应、减少血管内皮细胞凋亡及稳定颈动脉斑块发挥抗动脉粥样硬化(AS)作用。临床研究证实，PCSK9i联合他汀可降低主要心血管事件风险15%，并显著减少CI复发。近期研究还揭示了PCSK9i通过调控血管平滑肌细胞线粒体功能增强斑块稳定性的新机制。PCSK9i通过多途径协同作用，为CI的防治提供了新方向，但其长期疗效及个体化应用仍需进一步探索。未来，PCSK9i研究的重点在于推进新型药物的研发，探索联合用药与个体化治疗以及提升药品的普及性。

Abstract: Cerebral infarction (CI) is one of the main causes of death and disability worldwide, and its pathogenesis is closely related to low-density lipoprotein cholesterol mediated atherosclerosis (AS). Proprotein convertase subtilisin type 9 (PCSK9) inhibitor can significantly reduce the level of LDL-C by targeted inhibition of PCSK9 binding to low-density lipoprotein receptor (LDL-R), which has become a new strategy for the prevention and treatment of CI. This article reviews the mechanism of action of PCSK9 inhibitors (PCSK9i) and their pleiotropic effects in the prevention and treatment of CI. PCSK9i includes monoclonal antibody (mAb) preparations such as alirocumab and evolocumab, and small interfering RNA preparations such as inclisiran, which can achieve long-term lipid-lowering by blocking PCSK9 function or inhibiting its synthesis, respectively. In addition to lipid-lowering, PCSK9i can also play an anti atherosclerotic (AS) role by inhibiting the inflammatory response, reducing vascular endothelial cell apoptosis, and stabilizing carotid plaque. Clinical studies have confirmed that PCSK9i combined with statin can reduce the risk of major cardiovascular events by 15% and significantly reduce the recurrence of CI. Recent studies have also revealed a new mechanism by which PCSK9i enhances plaque stability by regulating mitochondrial function in vascular smooth muscle cells. PCSK9i provides a new direction for the prevention and treatment of CI through multi-channel synergy, but its long-term efficacy and individualized application still need further exploration. In the future, the focus of PCSK9 inhibitor research is to promote the research and development of new drugs, explore the combination and individualized treatment, and improve the popularity of drugs.