PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor

Dasom Shin, Soungchan Kim, Hwan Lee, Hyun-Chae Lee, Jaewon Lee, Hyun-woo Park, Mina Fukai, EunByule Choi, Subin Choi, Bon-Jun Koo, Ji-Hoon Yu, Gyurae No, Sungyoon Cho, Chan Woo Kim, Dohyun Han, Hyun-Duk Jang () and Hyo-Soo Kim ()
Additional contact information
Dasom Shin: Seoul National University Hospital
Soungchan Kim: Seoul National University Hospital
Hwan Lee: Seoul National University Hospital
Hyun-Chae Lee: Seoul National University Hospital
Jaewon Lee: Seoul National University Hospital
Hyun-woo Park: Seoul National University Hospital
Mina Fukai: Seoul National University Hospital
EunByule Choi: Seoul National University Hospital
Subin Choi: Seoul National University Hospital
Bon-Jun Koo: Seoul National University Hospital
Ji-Hoon Yu: Seoul National University Hospital
Gyurae No: Seoul National University Hospital
Sungyoon Cho: Seoul National University Hospital
Chan Woo Kim: Laboratory Animal Center, Osong Medical Innovation Foundation (KBIO)
Dohyun Han: Seoul National University Hospital
Hyun-Duk Jang: Seoul National University Hospital
Hyo-Soo Kim: Seoul National University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. Its blockers have emerged as promising therapeutics for cardiovascular diseases. Here we show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. PCSK9 exacerbates atherosclerosis in LDL receptor knockout mice. Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. We find spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) to be the key mediators of inflammation after PCSK9-CAP1 binding. In human peripheral blood mononuclear cells, serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. The CAP1-fragment crystallizable region (CAP1-Fc) mitigates PCSK9-mediated inflammatory signal transduction more than the PCSK9 blocking antibody evolocumab does.

Date: 2024
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DOI: 10.1038/s41467-024-46336-2

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