2. Academic Validation
  3. Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis

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

  • Elife. 2022 Jan 11:11:e72579. doi: 10.7554/eLife.72579.
Darian Williams # 1 2,  Marwa Mahmoud # 1,  Renfa Liu # 1 3,  Aitor Andueza 1,  Sandeep Kumar 1,  Dong-Won Kang 1,  Jiahui Zhang 1,  Ian Tamargo 2,  Nicolas Villa-Roel 1,  Kyung-In Baek 1,  Hwakyoung Lee 4,  Yongjin An 4,  Leran Zhang 5,  Edward W Tate 5,  Pritha Bagchi 6,  Jan Pohl 7,  Laurent O Mosnier 8,  Eleftherios P Diamandis 9,  Koichiro Mihara 10,  Morley D Hollenberg 10,  Zhifei Dai 3,  Hanjoong Jo 1 2 11
Affiliations

Affiliations

  • 1 Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States.
  • 2 Molecular and Systems Pharmacology Program, Emory University, Atlanta, United States.
  • 3 Department of Biomedical Engineering, Peking University, Beijing, China.
  • 4 Celltrion, Incheon, Republic of Korea.
  • 5 Department of Chemistry, Imperial College London, London, United Kingdom.
  • 6 Emory Integrated Proteomics Core, Emory University, Atlanta, United States.
  • 7 Biotechnology Core Facility Branch, Centers for Disease Control and Prevention, Atlanta, United States.
  • 8 Department of Molecular Medicine, Scripps Research Institute, San Diego, United States.
  • 9 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.
  • 10 Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada.
  • 11 Department of Medicine, Emory University, Atlanta, United States.
  • # Contributed equally.
PMID: 35014606 DOI: 10.7554/eLife.72579
Abstract

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.

Keywords

atherosclerosis; cell biology; endothelial cells; human; immunology; inflammation; kallikreins; mechanobiology; mouse; shear stress.

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