title: Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK.
abstract: The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H(2)O(2) generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H(2)O(2) generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms.
authors.affiliation: Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana; Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Jalahalli M
authors.initials: JM
authors.lastname: Siddesha
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Siva S V P
authors.initials: SS
authors.lastname: Sakamuri
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gardner
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.forename: Makoto
authors.initials: M
authors.lastname: Noda
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics*; D007797:Laminin / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000737:chemistry
chemical_list: D004338:Drug Combinations; D058851:GPI-Linked Proteins; D020382:Interleukin-18; D007797:Laminin; D011509:Proteoglycans; C115460:RECK protein, human; C059485:matrigel; D003094:Collagen; D006861:Hydrogen Peroxide; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D001241:Aspirin