Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor

Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role LRG1 endothelial activation. cells (ECs) arteries critical limb ischemia (CLI) was assessed by immunohistochemistry ELISA, respectively. expression sheared tumor necrosis factor-α (TNF-α)-treated ECs analyzed. The mechanistic activation studied vitro . Plasma 37-week-old Lrg1 –/– mice used causality between factor receptor 1 (TNFR1) shedding. highly expressed stenotic but not normal arteries. CLI were elevated compared healthy controls. shear dependent. It could be induced TNF-α, induction its mediated NF-κB inhibited TNF-α-induced signaling, VCAM-1 ICAM-1, monocyte capture, firm adhesion, transendothelial migration. Mechanistically, exerted function causing shedding TNFR1 via ALK5-SMAD2 pathway subsequent ADAM10. Consistent this mechanism, sTNFR1 correlated patients. Causality established showing that had lower plasma than wild type mice. Our results demonstrate a novel for potential therapeutic inflammatory diseases should investigated further.