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

Meixin Zhang; Yixi Chen; Yumin Qiu; Jiapan Sun; Jiang He; Zhefu Liu; Jian Shi; Wenbin Wei; Guifu Wu; Jianwen Liang

doi:10.1016/j.jacbts.2023.05.016

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

JACC Basic Transl Sci. 2023 Aug 30;8(9):1060-1077. doi: 10.1016/j.jacbts.2023.05.016. eCollection 2023 Sep.

Authors

Meixin Zhang¹, Yixi Chen¹, Yumin Qiu², Jiapan Sun³, Jiang He², Zhefu Liu², Jian Shi¹, Wenbin Wei¹, Guifu Wu¹, Jianwen Liang¹

Affiliations

¹ Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
² Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
³ Department of Geriatrics, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China.

Abstract

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.

Keywords: PCSK9; Smac; critical limb ischemia; pyroptosis; vascular endothelial cell.