Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis
- Elife. 2022 Jan 11:11:e72579. doi: 10.7554/eLife.72579.
- 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.
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.