The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol.

IF 4.5 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Heart Failure Reviews Pub Date : 2024-09-01 Epub Date: 2024-06-18 DOI:10.1007/s10741-024-10409-7
Mieczysław Dutka, Karolina Zimmer, Michał Ćwiertnia, Tomasz Ilczak, Rafał Bobiński
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Abstract

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases.

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PCSK9 在心力衰竭和其他心血管疾病中的作用--除了对低密度脂蛋白胆固醇的影响之外的作用机制。
Proprotein convertase subtilisin/kexin type-9 (PCSK9)是一种通过与肝脏低密度脂蛋白受体(LDLR)结合来调节低密度脂蛋白(LDL)胆固醇代谢的蛋白质,最终导致其溶酶体降解和低密度脂蛋白胆固醇(LDLc)水平升高。目前已开发出通过特异性抗体(alirocumab、evolocumab)阻断 PCSK9 和通过小调控 RNA(siRNA)(inclisiran)阻断 PCSK9 生成的治疗策略。评估这些药物的临床试验证实,它们在降低动脉粥样硬化性心血管疾病患者血清低密度脂蛋白胆固醇(LDLc)水平和改善预后方面具有很高的疗效。大多数研究侧重于 PCSK9 对 LDLRs 的作用以及随后 LDLc 浓度的增加。越来越多的证据表明,PCSK9 对心血管的不良影响,尤其是对血管壁的动脉粥样硬化影响,也可能来自于其对脂质代谢影响之外的机制。PCSK9 可诱导促炎细胞因子的表达,导致血管壁发炎,并促进心肌细胞凋亡、热凋亡和铁凋亡,从而参与心力衰竭的发生和发展。因此,消除 PCSK9 不仅可以治疗高胆固醇血症,还可以治疗动脉粥样硬化和其他心血管疾病。PCSK9在心血管系统中的作用机制尚未完全明了。本文回顾了目前对 PCSK9 在心血管系统中的作用机制及其对心血管疾病的影响的认识。对这些机制的了解可能有助于在治疗心血管疾病时更广泛地使用 PCSK9 抑制剂。
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来源期刊
Heart Failure Reviews
Heart Failure Reviews 医学-心血管系统
CiteScore
10.40
自引率
2.20%
发文量
90
审稿时长
6-12 weeks
期刊介绍: Heart Failure Reviews is an international journal which develops links between basic scientists and clinical investigators, creating a unique, interdisciplinary dialogue focused on heart failure, its pathogenesis and treatment. The journal accordingly publishes papers in both basic and clinical research fields. Topics covered include clinical and surgical approaches to therapy, basic pharmacology, biochemistry, molecular biology, pathology, and electrophysiology. The reviews are comprehensive, expanding the reader''s knowledge base and awareness of current research and new findings in this rapidly growing field of cardiovascular medicine. All reviews are thoroughly peer-reviewed before publication.
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