title: FasL expression in cardiomyocytes activates the ERK1/2 pathway, leading to dilated cardiomyopathy and advanced heart failure.
abstract: Increase in the apoptotic molecule Fas ligand (FasL) in serum and cardiomyocytes has been shown to be associated with progressive dilated cardiomyopathy (DCM) and congestive heart failure (CHF) in humans. However, the underlying mechanism(s) of FasL-related deterioration of heart function remain obscure. The aim of the present study is to determine roles of myocardial FasL in the activation of alternative pathways such as extracellular-signal-regulated kinase 1/2 (ERK1/2), inflammation or fibrosis and to identify effective treatments of progressive DCM and advanced CHF. Transgenic mice with cardiomyocyte-specific overexpression of FasL were investigated and treated with an ERK1/2 inhibitor (U-0126), losartan (los), prednisolone (pred) or placebo. Morpho-histological and molecular studies were subsequently performed. FasL mice showed significantly higher mortality compared with wild-type (WT) littermates due to DCM and advanced CHF. Prominent perivascular and interstitial fibrosis, increased interleukin secretion and diffuse CD3-positive cell infiltration were evident in FasL hearts. Up-regulation of the short form of Fas-associated death domain (FADD)-like interleukin 1β-converting enzyme (FLICE) inhibitory protein (s-FLIP), RIP (receptor-interacting protein) and ERK1/2 and down-regulation of transforming growth factor beta 1 (TGFβ1) and nuclear factor-κB (NF-κB) was determined in the myocardium, whereas expression of ERK1/2, periostin (Postn) and osteopontin increased in cardiac fibroblasts. U-0126 and los increased CHF survival by 75% compared with pred and placebo groups. U-0126 had both anti-fibrotic and anti-apoptotic effects, whereas los reduced fibrosis only. Myocardial FasL expression in mice activates differential robust fibrotic, apoptotic and inflammatory responses via ERK1/2 in cardiomyocytes and cardiac fibroblasts inducing DCM and CHF. Blocking the ERK1/2 pathway prevented progression of FasL-induced DCM and CHF by reducing fibrosis, inflammation and apoptosis in the myocardium.
authors.affiliation: Texas Heart Institute, Regenerative Medicine Research, Houston, TX 77030, U.S.A. Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, U.S.A.
authors.forename: Anne-Cecile
authors.initials: AC
authors.lastname: Huby
authors.affiliation: Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, U.S.A. Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, U.S.A.
authors.forename: Subat
authors.initials: S
authors.lastname: Turdi
authors.affiliation: Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, U.S.A.
authors.forename: Jeanne
authors.initials: J
authors.lastname: James
authors.affiliation: Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, U.S.A. Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, U.S.A.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.affiliation: Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, U.S.A. Department of Pediatrics, The Heart Institute, University of Tennessee Health Science Center, Memphis, TN 38103, U.S.A. epurevjav@uthsc.edu.
authors.forename: Enkhsaikhan
authors.initials: E
authors.lastname: Purevjav
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D018450:Disease Progression; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERK1/2; Fas-ligand; apoptosis; congestive heart failure; fibrosis