Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis
| Autor: | Renfa Liu, Marwa Mahmoud, Darian Williams, 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 |
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| Přispěvatelé: | Cancer Research UK |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
kallikreins QH301-705.5 Science 0601 Biochemistry and Cell Biology General Biochemistry Genetics and Molecular Biology shear stress immunology Immunology and Inflammation cell biology Animals human Biology (General) mouse General Immunology and Microbiology General Neuroscience General Medicine mechanobiology endothelial cells Mice Inbred C57BL Gene Expression Regulation inflammation Medicine atherosclerosis Research Article |
| Zdroj: | eLife, Vol 11 (2022) eLife |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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