Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis
Year: 2022
Type: article
Abstract: Introduction 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 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 arterial endothelial cells, but its role in endothelial biology and atherosclerosis was unknown. Methods and Results 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 endothelial cells (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 inflammation and permeability dysfunction in human artery ECs (HAECs). Further, 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. Studies using pharmacological inhibitors and siRNAs revealed that the anti-inflammatory effects of KLK10 were mediated by a Protease Activated Receptors (PAR1/2)-dependent manner. However, unexpectedly, KLK10 did not cleave the PARs. Through a proteomics study, we identified HTRA1 (High-temperature requirement A serine peptidase 1), which bound and cleaved KLK10. Further, siRNA knockdown of HTRA1 prevented KLK10’s anti-inflammatory and barrier protective function in HAECs, suggesting that HTRA1 regulates KLK10 function. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques. Conclusion KLK10 is a flow-sensitive endothelial protein and, in collaboration with HTRA1, serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.
Source: eLife
DOI: 10.7554/elife.72579
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. Diamandis, Koichiro Mihara, Morley D. Hollenberg, Zhifei Dai, Hanjoong Jo
Institutions: Georgia Institute of Technology, Emory University, The Wallace H. Coulter Department of Biomedical Engineering, Peking University, Celltrion (South Korea), Imperial College London, Centers for Disease Control and Prevention, Scripps Research Institute, Mount Sinai Hospital, University of Toronto, University of Calgary
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: HEG1 in endothelial function and atherosclerosis, Medical Scientist Training Program, G2501474049, G252106449, G2619331999, Structure-function of cytoprotective coagulation proteases and their receptors, Role of flow-sensitive KLK10 in endothelial dysfunction and atherosclerosis, Shear stress, endothelial miRNAs, and AV calcification, Role of KLK10 in Endothelial Biology and Atherosclerosis, Novel functions of Thrombin Activatable Fibrinolysis Inhibitor (TAFI), G746098578, Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease, Regulation of Protein C Pathways, Graduate Training in the Pharmacological Sciences
OpenAlex ID: W4225972012