Endothelial Cell-Derived PCSK9 in Atherosclerosis: Pathophysiological Roles and Therapeutic Perspectives

Atherosclerosis (AS), the primary pathological basis for cardiovascular disease (CVD), is initiated by endothelial dysfunction. This review aimed to summarize the current understanding of endothelial cell-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) in the pathogenesis of AS and to explore the potential of using PCSK9 as a therapeutic target. Endothelial PCSK9 contributes to AS progression by regulating lipid metabolism through low-density lipoprotein receptor (LDLR) degradation and promoting inflammatory responses, oxidative stress, endothelial apoptosis, and increased vascular permeability. Recent evidence indicates that endothelial-derived PCSK9 is upregulated under pathological conditions and exerts multiple atherogenic effects independent of circulating PCSK9. Experimental studies have demonstrated that silencing or inhibiting endothelial PCSK9 alleviates endothelial dysfunction, reduces plaque development, and mitigates inflammatory responses. Moreover, PCSK9 may modulate the redox balancing and cellular signaling pathways involved in vascular homeostasis. Endothelial PCSK9 plays a critical role in the initiation and progression of AS through mechanisms beyond lipid regulation. Targeting endothelial PCSK9 may represent a novel and promising strategy for preventing and treating AS, warranting further preclinical and clinical investigation.