title: FSP-1 Impairs the Function of Endothelium Leading to Failure of Arteriovenous Grafts in Diabetic Mice.
abstract: To understand how endothelial cell (EC) dysfunction contributes to the failure of arteriovenous graft (AVG), we investigated the role of fibroblast-specific protein 1 (FSP-1) in cultured ECs and a mouse AVG model. In vitro, we uncovered a new FSP-1-dependent pathway that activates rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) in ECs, leading to phosphorylation of myosin light chain 2 resulting in EC dysfunction. In cultured ECs, high glucose stimulated FSP-1 expression and increased permeability of an EC monolayer. The increase in permeability by the high glucose concentration was mediated by FSP-1 expression. Treatment of cultured ECs with FSP-1 caused leakage of the endothelial barrier plus increased expression of adhesion molecules and decreased expression of junction molecules. These responses were initiated by binding of FSP-1 to receptor for advanced glycation end products, which resulted in ROCK1 activation. In vivo, diabetes increased infiltration of inflammatory cells into AVGs and stimulated neointima formation. Increased FSP-1 expression and ROCK1 activation were found in AVGs of diabetic mice. Blocking FSP-1 suppressed diabetes-induced ROCK1 activation in AVGs. In mice with FSP-1 knockout or with ROCK1 knockout, accumulation of inflammatory cells and neointima formation in AVG were attenuated despite diabetes. Thus, mechanisms of inhibiting FSP-1 in ECs could improve AVG function.
authors.affiliation: Nephrology Division (J.L., M.L., W.E.M., M.Y., J.C.), Baylor College of Medicine, Houston, Texas 77030; Emergency Medicine (F.R.D.), University of Texas MD Anderson Cancer Center, Houston, Texas 77030; and Department of Emergency (J.L.), Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China 430074.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Luo
authors.forename: Ming
authors.initials: M
authors.lastname: Liang
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.forename: Farhad R
authors.initials: FR
authors.lastname: Danesh
authors.forename: Michael
authors.initials: M
authors.lastname: Yu
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D024722:Cardiac Myosins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D011183:Postoperative Complications / Q000235:genetics / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018994:Myosin Light Chains; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C107184:myosin light chain 2; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D024722:Cardiac Myosins