Gao Yue, Zhang Jing, Jiang Nan, Wang Lijuan, Cao Tingbing, Xie Yangli, He Hongbo, Li Li
Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Army Specialty Medical Center, Army Medical University, Chongqing, China.
Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR), State Key Laboratory of Trauma and Chemical Poisoning, Army Specialty Medical Center, Army Medical University, Chongqing, China.
Sci Prog. 2025 Jul-Sep;108(3):368504251370679. doi: 10.1177/00368504251370679. Epub 2025 Sep 16.
This narrative review comprehensively examines the multifaceted roles of proprotein convertase subtilisin/kexin type 9 (PCSK9) in peripheral arterial disease (PAD). PCSK9, a key enzymatic regulator of lipid metabolism, binds to low-density lipoprotein receptors (LDLRs) and promotes their degradation, thereby increasing plasma low-density lipoprotein cholesterol (LDL-C) levels. This mechanism establishes PCSK9 as a critical driver of atherosclerosis and PAD. Emerging evidence indicates that the role of PCSK9 in PAD extended beyond its traditional lipid-modulating functions. Specifically, PCSK9 gene polymorphisms have been shown to significantly increase PAD susceptibility, while elevated plasma PCSK9 is an independent PAD risk factor and correlates positively with disease severity. Mechanistic studies revealed that PCSK9 directly participated in vascular pathological processes through multiple pathways, some of which are independent of LDLR-mediated effects. Current clinical applications have demonstrated that PCSK9 inhibitors confer clinically meaningful therapeutic benefits in PAD patients, including reduced risks of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). In particular, some of these clinical benefits may be attributed to improvements in endothelial function and microcirculatory perfusion. However, the therapeutic strategies involving PCSK9 inhibitors face persistent challenges, such as determining optimal dosing timelines, assessing long-term safety, and exploring synergies with other therapies. Future studies should prioritize large-scale randomized controlled trials to elucidate the molecular mechanisms underlying PCSK9's roles in vascular calcification and inflammatory microenvironments. Additionally, advancing the precision interventions targeting PCSK9 is essential for advancing comprehensive management approaches for PAD.
本叙述性综述全面探讨了前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）在周围动脉疾病（PAD）中的多方面作用。PCSK9是脂质代谢的关键酶调节剂，它与低密度脂蛋白受体（LDLR）结合并促进其降解，从而提高血浆低密度脂蛋白胆固醇（LDL-C）水平。这一机制使PCSK9成为动脉粥样硬化和PAD的关键驱动因素。新出现的证据表明，PCSK9在PAD中的作用超出了其传统的脂质调节功能。具体而言，已表明PCSK9基因多态性会显著增加PAD易感性，而血浆PCSK9升高是独立的PAD危险因素，且与疾病严重程度呈正相关。机制研究表明，PCSK9通过多种途径直接参与血管病理过程，其中一些途径独立于LDLR介导的效应。目前的临床应用表明，PCSK9抑制剂在PAD患者中具有临床意义的治疗益处，包括降低主要不良心血管事件（MACE）和主要不良肢体事件（MALE）的风险。特别是，其中一些临床益处可能归因于内皮功能和微循环灌注的改善。然而，涉及PCSK9抑制剂的治疗策略面临持续挑战，如确定最佳给药时间、评估长期安全性以及探索与其他疗法的协同作用。未来的研究应优先开展大规模随机对照试验，以阐明PCSK9在血管钙化和炎症微环境中作用的分子机制。此外，推进针对PCSK9的精准干预对于推进PAD的综合管理方法至关重要。
