title: Activated Factor X Induces Endothelial Cell Senescence Through IGFBP-5.
abstract: Uncontrolled coagulation contributes to the pathophysiology of several chronic inflammatory diseases. In these conditions, senescent cells are often observed and is involved in the generation of inflammation. The coincidence of hyper-coagulation, cell senescence, and inflammation suggests the existence of a common underlying mechanism. Recent evidence indicates that activated coagulation factor X (FXa) plays a role in the processes beyond blood coagulation. This non-hematologic function entails the mediation of inflammation and tissue remodeling. We therefore tested the hypothesis that FXa induces cell senescence resulting in tissue inflammation and impaired tissue regeneration. Human umbilical vein endothelial cells were stimulated with FXa for 14 days. The proliferation of cells treated with FXa was significantly smaller, and the fraction of senescence-associated β-galactosidase-positive cells was increased as compared to the control group. RT-qPCR array revealed that FXa increased the expression of IGFBP-5, EGR-1, p53, and p16INK4a. Inhibition of FXa by a direct FXa inhibitor, rivaroxaban, or IGFBP-5 by siRNA decreased FXa-induced cell senescence, restoring cell proliferation. Moreover, in an ischemic hind limb mouse model, FXa inhibited neovascularization by endothelial progenitor cell. However, rivaroxaban significantly restored FXa-induced impaired angiogenesis. In summary, FXa induced endothelial cell senescence through IGFBP-5, resulting in impaired angiogenesis.
authors.affiliation: Department of Clinical Gene Therapy, Suita, Osaka 565-0871, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.affiliation: Department of Clinical Gene Therapy, Suita, Osaka 565-0871, Japan.|Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.affiliation: Department of Clinical Gene Therapy, Suita, Osaka 565-0871, Japan.|Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Muratsu
authors.affiliation: Department of Clinical Gene Therapy, Suita, Osaka 565-0871, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Otsu
authors.affiliation: Department of Clinical Gene Therapy, Suita, Osaka 565-0871, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwabayashi
authors.affiliation: Department of Clinical Gene Therapy, Suita, Osaka 565-0871, Japan.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carracedo
authors.affiliation: Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.affiliation: Department of Clinical Gene Therapy, Suita, Osaka 565-0871, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D015951:Factor Xa / Q000008:administration & dosage / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects
chemical_list: D016207:Cytokines; D018975:Insulin-Like Growth Factor Binding Protein 5; D015951:Factor Xa