title: Lipopolysaccharide Activates Toll-Like Receptor 4 and Prevents Cardiac Fibroblast-to-Myofibroblast Differentiation.
abstract: Bacterial lipopolysaccharide (LPS) is a known ligand of Toll-like receptor 4 (TLR4) which is expressed in cardiac fibroblasts (CF). Differentiation of CF to cardiac myofibroblasts (CMF) is induced by transforming growth factor-β1 (TGF-β1), increasing alpha-smooth muscle actin (α-SMA) expression. In endothelial cells, an antagonist effect between LPS-induced signaling and canonical TGF-β1 signaling was described; however, it has not been studied whether in CF and CMF the expression of α-SMA induced by TGF-β1 is antagonized by LPS and the mechanism involved. In adult rat CF and CMF, α-SMA, ERK1/2, Akt, NF-κβ, Smad3, and Smad7 protein levels were determined by western blot, TGF-β isoforms by ELISA, and α-SMA stress fibers by immunocytochemistry. CF and CMF secrete the three TGF-β isoforms, and the secretion levels of TGF-β2 was affected by LPS treatment. In CF, LPS treatment decreased the protein levels of α-SMA, and this effect was prevented by TAK-242 (TLR4 inhibitor) and LY294002 (Akt inhibitor), but not by BAY 11-7082 (NF-κβ inhibitor) and PD98059 (ERK1/2 inhibitor). TGF-β1 increased α-SMA protein levels in CF, and LPS prevented partially this effect. In addition, in CMF α-SMA protein levels were decreased by LPS treatment, which was abolished by TAK-242. Finally, in CF LPS decreased the p-Smad3 phosphorylation and increased the Smad7 protein levels. LPS treatment prevents the CF-to-CMF differentiation and reverses the CMF phenotype induced by TGF-β1, through decreasing p-Smad3 and increasing Smad7 protein levels.
authors.affiliation: Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.|Faculty of Chemistry and Pharmacy, Atlantic University, Barranquilla, Colombia.
authors.forename: Samir
authors.initials: S
authors.lastname: Bolívar
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Roxana
authors.initials: R
authors.lastname: Santana
authors.affiliation: Center of Medical Investigations, Catholic University of Chile, Santiago, Chile.
authors.forename: Pedro
authors.initials: P
authors.lastname: Ayala
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Landaeta
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Pía
authors.initials: P
authors.lastname: Boza
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Humeres
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Raúl
authors.initials: R
authors.lastname: Vivar
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Claudia
authors.initials: C
authors.lastname: Muñoz
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Viviana
authors.initials: V
authors.lastname: Pardo
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Samuel
authors.initials: S
authors.lastname: Fernandez
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
authors.forename: Renatto
authors.initials: R
authors.lastname: Anfossi
authors.affiliation: Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, University of Chile, 8380492, Santiago, Chile. gadiaz@ciq.uchile.cl.|Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile. gadiaz@ciq.uchile.cl.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Diaz-Araya
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D058628:Myofibroblasts / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4
keywords: Cardiac fibroblast; Lipopolysaccharide; TLR4; α-SMA