title: Tissue-type plasminogen activator suppresses activated stellate cells through low-density lipoprotein receptor-related protein 1.
abstract: Hepatic stellate cell (HSC) activation and trans-differentiation into myofibroblast (MFB)-like cells is key for fibrogenesis after liver injury and a potential therapeutic target. Recent studies demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1)-dependent signaling by tissue-type plasminogen activator (t-PA) is a pro-fibrotic regulator of the MFB phenotype in kidney. This study investigated whether LRP1 signaling by t-PA is also relevant to HSC activation following injury. Primary and immortalized rat HSCs were treated with t-PA and assayed by western blot, MTT, and TUNEL. In vitro results were then verified using an in vivo, acute carbon tetrachloride (CCl4) injury model that examined the phenotype and recovery kinetics of MFBs from wild-type animals vs mice with a global (t-PA) or HSC-targeted (LRP1) deletion. In vitro, in contrast to kidney MFBs, exogenous, proteolytically inactive t-PA suppressed, rather than induced, activation markers in HSCs following phosphorylation of LRP1. This process was mediated by LRP1 as inhibition of t-PA binding to LRP1 blocked the effects of t-PA. In vivo, following acute injury, phosphorylation of LRP1 on activated HSCs occurred immediately prior to their disappearance. Mice lacking t-PA or LRP1 retained higher densities of activated HSCs for a longer time period compared with control mice after injury cessation. Hence, t-PA, an FDA-approved drug, contributes to the suppression of activated HSCs following injury repair via signaling through LRP1. This renders t-PA a potential target for exploitation in treating patients with fibrosis.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Liang-I
authors.initials: LI
authors.lastname: Kang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Koral
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Bowen
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Selen
authors.initials: S
authors.lastname: Muratoglu
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Mars
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D012997:Solvents / Q000737:chemistry / Q000633:toxicity; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011994:Recombinant Proteins; D012997:Solvents; D002251:Carbon Tetrachloride; D010959:Tissue Plasminogen Activator