title: Cathelicidin antimicrobial peptide inhibits fibroblast migration via P2X7 receptor signaling.
abstract: Fibrosis is one of the most common pathological alterations in heart failure, and fibroblast migration is an essential process in the development of cardiac fibrosis. Experimental autoimmune myocarditis (EAM) is a model of inflammatory heart disease characterized by inflammatory cell infiltration followed by healing without residual fibrosis. However, the precise mechanisms mediating termination of inflammation and nonfibrotic healing remain to be elucidated. Microarray analysis of hearts from model mice at multiple time points after EAM induction identified several secreted proteins upregulated during nonfibrotic healing, including the anti-inflammatory cathelicidin antimicrobial peptide (CAMP). Treatment with LL-37, a human homolog of CAMP, activated MAP kinases in fibroblasts but not in cardiomyocytes, indicating that fibroblasts were the target of CAMP activity. In addition, LL-37 decreased fibroblast migration in the in vitro scratch assay. P2X7 receptor (P2X7R), a well-known receptor for LL-37, was involved in LL-37 mediated biological effect on cardiac fibroblasts. Stimulation of BzATP, a P2X7R agonist, activated MAPK in fibroblasts, whereas the P2X7R antagonist, BBG, as well as P2X7R deletion abolished both LL-37-mediated MAPK activation and LL-37-induced reduction in fibroblast migration. These results strongly suggest that CAMP upregulation during myocarditis prevents myocardial fibrosis by restricting fibroblast migration via activation of the P2X7R-MAPK signaling pathway.
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kumagai
authors.forename: Kazuki
authors.initials: K
authors.lastname: Matsui
authors.forename: Haruyo
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Tomomi
authors.initials: T
authors.lastname: Mohri
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002465:Cell Movement; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction; D054804:Cathelicidins
chemical_list: D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; D058486:Receptors, Purinergic P2X7; D054804:Cathelicidins
keywords: CAMP; Cardiac fibroblast; Fibrosis; Myocarditis; P2X7 purinergic receptor