Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis.
Darian WilliamsMarwa MahmoudRenfa LiuAitor AnduezaSandeep KumarDong-Won KangJiahui ZhangIan TamargoNicolas Villa-RoelKyung-In BaekHwakyoung LeeYongjin AnLeran ZhangEdward W TatePritha BagchiJan PohlLaurent O MosnierEleftherios P DiamandisKoichiro MiharaMorley D HollenbergZhifei DaiHanjoong JoPublished in: eLife (2022)
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.
Keyphrases
- endothelial cells
- gene expression
- oxidative stress
- mouse model
- single cell
- poor prognosis
- high glucose
- blood flow
- cardiovascular disease
- magnetic resonance imaging
- cell adhesion
- dna methylation
- pseudomonas aeruginosa
- immune response
- anti inflammatory
- metabolic syndrome
- dendritic cells
- coronary artery disease
- cystic fibrosis
- multidrug resistant
- high fat diet
- early onset
- toll like receptor
- drug induced
- mild cognitive impairment
- small molecule
- peripheral blood
- rna seq
- skeletal muscle
- lps induced
- insulin resistance
- amino acid