신다솜 (서울대학교) | 한빛사논문 > 한빛사

한빛사논문

조회544

서울대학교

Nat. Commun., Mar 30 2024, 15 (1) | https://doi.org/10.1038/s41467-024-46336-2 PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor

Dasom Shin^1,2,3,7, Soungchan Kim^1,2,3,7, Hwan Lee^1,2,3,7, Hyun-Chae Lee^1,2, Jaewon Lee^1,2, Hyun-woo Park^1,2,4, Mina Fukai^1,2,3, EunByule Choi^1,2,3, Subin Choi^1,2,3, Bon-Jun Koo^1,2,3, Ji-Hoon Yu^1,2,3, Gyurae No^1,2,3, Sungyoon Cho^1,2,4, Chan Woo Kim⁵, Dohyun Han², Hyun-Duk Jang^1,2,8 & Hyo-Soo Kim^1,3,4,6,8

¹Center of CBT (Cell and BioTherapy), Seoul National University Hospital, Seoul, Republic of Korea.

²Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.

³Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

⁴Program in Stem Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.

⁵Department of Preclinical Trial, Laboratory Animal Center, Osong Medical Innovation Foundation (KBIO), Cheongju, Chungbuk, Republic of Korea.

⁶Cardiovascular Center & Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

⁷These authors contributed equally: Dasom Shin, Soungchan Kim, Hwan Lee.

⁸These authors jointly supervised this work: Hyun-Duk Jang, Hyo-Soo Kim.

Corresponding authors : Correspondence to Hyun-Duk Jang or Hyo-Soo Kim.

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.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-04-01)
연구진국내 연구진
분야 의약학 > 응용의학

댓글 작성 로그인

CV 열람하기

연락처 보기