Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis

eLife

Jan Pohl¹  Hwakyoung Lee²  Yongjin An²  Marwa Mahmoud³  Nicolas Villa-Roel³  Sandeep Kumar³  Aitor Andueza³  Jiahui Zhang³  Dong-Won Kang³  Kyung-In Baek³  Renfa Liu⁴  Darian Williams⁵  Hanjoong Jo⁶  Zhifei Dai⁷  Edward W Tate⁸  Leran Zhang⁸  Laurent O Mosnier⁹  Eleftherios P Diamandis^1,10  Koichiro Mihara^1,11  Morley D Hollenberg^1,11  Pritha Bagchi^1,12  Ian Tamargo^1,13 

[1] Biotechnology Core Facility Branch, Centers for Disease Control and Prevention, Atlanta, United States;Celltrion, Incheon, Republic of Korea;Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States;Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States;Department of Biomedical Engineering, Peking University, Beijing, China;Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States;Molecular and Systems Pharmacology Program, Emory University, Atlanta, United States;Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States;Molecular and Systems Pharmacology Program, Emory University, Atlanta, United States;Department of Medicine, Emory University, Atlanta, United States;Department of Biomedical Engineering, Peking University, Beijing, China;Department of Chemistry, Imperial College London, London, United Kingdom;Department of Molecular Medicine, Scripps Research Institute, San Diego, United States;Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada;Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada;Emory Integrated Proteomics Core, Emory University, Atlanta, United States;Molecular and Systems Pharmacology Program, Emory University, Atlanta, United States;

关键词: atherosclerosis;    kallikreins;    mechanobiology;    shear stress;    endothelial cells;    inflammation;    Human;    Mouse;   

DOI  :  10.7554/eLife.72579

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell (EC) gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified kallikrein-related peptidase 10 (Klk10, a secreted serine protease) as a flow-sensitive gene in mouse arterial ECs, but its role in endothelial biology and atherosclerosis was unknown. Here, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo mouse models and in vitro studies with cultured ECs. Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated Klk10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced permeability dysfunction and inflammation in human artery ECs, as determined by NFκB activation, expression of vascular cell adhesion molecule 1 and intracellular adhesion molecule 1, and monocyte adhesion. Furthermore, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of Klk10-expressing plasmids inhibited atherosclerosis in Apoe−/− mice. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques. KLK10 is a flow-sensitive endothelial protein that serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.

【 授权许可】

CC BY