PCSK9 Promotes Hypoxia-Induced EC Pyroptosis by Regulating Smac Mitochondrion-Cytoplasm Translocation in Critical Limb Ischemia

[Display omitted] •Hypoxia-induced EC death and impaired angiogenesis are the main pathophysiological features of CLI. However, existing treatments have failed to significantly improve CLI. Therefore, it is necessary to deeply explore the mechanism underlying angiogenic dysfunction in ischemia.•PCSK9 expression was significantly up-regulated in hypoxic ECs. The level of PCSK9 was elevated in patients with CLI. Suppressing the expression of PCSK9 attenuated hypoxia-induced pyroptosis and impaired angiogenesis. Mechanistically, PCSK9 aggravates hypoxia-induced vascular EC pyroptosis by regulating Smac mitochondrion-cytoplasm translocation in CLI.•Additional studies will be required to clarify how PCSK9 mediates Smac mitochondria-cytoplasm translocation in HUVECs. In addition, whether the application of PCSK9 inhibitor could contribute to recovery in CLI also merits further clinical study and validation. Hypoxia-induced endothelial cell death and impaired angiogenesis are the main pathophysiological features of critical limb ischemia. Mechanistically, proprotein convertase subtilisin/kexin type 9 (PCSK9) promoted Smac translocation from mitochondria to the cytoplasm. Inhibition of Smac release into the cytoplasm attenuated PCSK9-mediated hypoxia-induced pyroptosis. Functionally, PCSK9 overexpression impaired angiogenesis in vitro and reduced blood perfusion in mice with lower limb ischemia, but the effect was reversed by PCSK9 inhibition. This study demonstrates that PCSK9 aggravates pyroptosis by regulating Smac mitochondrion-cytoplasm translocation in the vascular endothelium, providing novel insights into PCSK9 as a potential therapeutic target in critical limb ischemia.