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

• DOI: 10.7554/elife.72579
• Publication Date: 2022-01-11T13:00:46Z
• Authors: Darian Williams; Marwa Mahmoud; Renfa Liu; Aitor Andueza; Sandeep Kumar; Dong-Won Kang; Jiahui Zhang; Ian Tamargo; Nicolas Villa-Roel; Kyung-In Baek; Hwakyoung Lee; Yongjin An; Leran Zhang; Edward W Tate; Pritha Bagchi; Jan Pohl; Laurent O Mosnier; Eleftherios P Dia...; Koichiro Mihara; Morley D Hollenberg; Zhifei Dai; Hanjoong Jo
• Keywords: Endothelial Dysfunction; Endothelial Activation

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