BibTex format
@article{Williams:2022:10.7554/eLife.72579,
author = {Williams, D and Mahmoud, M and Liu, R and Andueza, A and Kumar, S and Kang, D-W and Zhang, J and Tamargo, I and Villa-Roel, N and Baek, K-I and Lee, H and An, Y and Zhang, L and Tate, EW and Bagchi, P and Pohl, J and Mosnier, LO and Diamandis, EP and Mihara, K and Hollenberg, MD and Dai, Z and Jo, H},
doi = {10.7554/eLife.72579},
journal = {eLife},
pages = {1--23},
title = {Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis.},
url = {http://dx.doi.org/10.7554/eLife.72579},
volume = {11},
year = {2022}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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 mouse arterial endothelial cells, 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 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 permeability dysfunction and inflammation in human artery ECs (HAECs), as determined by NFkB activation, expression of vascular cell adhesion molecule 1 (VCAM1) and intracellular adhesion molecule 1 (ICAM1), and monocyte adhesion. 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. 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.
AU - Williams,D
AU - Mahmoud,M
AU - Liu,R
AU - Andueza,A
AU - Kumar,S
AU - Kang,D-W
AU - Zhang,J
AU - Tamargo,I
AU - Villa-Roel,N
AU - Baek,K-I
AU - Lee,H
AU - An,Y
AU - Zhang,L
AU - Tate,EW
AU - Bagchi,P
AU - Pohl,J
AU - Mosnier,LO
AU - Diamandis,EP
AU - Mihara,K
AU - Hollenberg,MD
AU - Dai,Z
AU - Jo,H
DO - 10.7554/eLife.72579
EP - 23
PY - 2022///
SN - 2050-084X
SP - 1
TI - Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis.
T2 - eLife
UR - http://dx.doi.org/10.7554/eLife.72579
UR - https://www.ncbi.nlm.nih.gov/pubmed/35014606
UR - https://elifesciences.org/articles/72579
UR - http://hdl.handle.net/10044/1/94283
VL - 11
ER -
