title: Fibroblast growth factor 21 protects the heart from oxidative stress.
abstract: OBJECTIVE
  Oxidative stress mediated by reactive oxygen species (ROS) plays a striking role in the pathogenesis of heart failure, and antioxidants have been shown to attenuate cardiac remodelling in experimental models of cardiac damage. We recently showed that fibroblast growth factor 21 (Fgf21) is produced by the heart and exerts protective effects, preventing cardiac hypertrophy development. The aim of the study was to determine the effects of Fgf21 during oxidative stress signalling in the heart.
  
  
  RESULTS
  Fgf21 treatment in cardiomyocytes in culture induced the expression of genes encoding proteins involved in antioxidative pathways, including mitochondrial uncoupling proteins (Ucp2 and Ucp3) and superoxide dismutase-2 (Sod2) and reduced ROS production. In keeping with this, expression of antioxidant genes in response to lipopolysaccharide (LPS)-induced stimulation of pro-inflammatory pathways or isoproterenol-induced cardiac hypertrophy in the heart was reduced in Fgf21-null mice. Moreover, we found that Fgf21 is expressed in and released by cardiomyocytes in response to LPS, and its expression is under the control of the Sirt1 (sirtuin-1) pathway. This Fgf21 released by cardiomyocytes acts in an autocrine manner to protect cells against oxidative stress. Finally, failing human hearts showed up-regulation of Fgf21, Ucp3, and Sod2, confirming the association between Fgf21 induction and the control of cardiac oxidative stress pathways.
  
  
  CONCLUSIONS
  Our data indicate that Fgf21 regulates genes involved in antioxidant pathways in an autocrine manner, thus preventing ROS production in cardiac cells. Therefore, Fgf21 acts as an antioxidant factor in the heart, preventing induction of pro-oxidative pathways by inflammatory or hypertrophic conditions.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Avda Diagonal 643, Barcelona 08028, Spain aplanavila@ub.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Planavila
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Avda Diagonal 643, Barcelona 08028, Spain.
authors.forename: Ibon
authors.initials: I
authors.lastname: Redondo-Angulo
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Avda Diagonal 643, Barcelona 08028, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Ribas
authors.affiliation: Laboratory of Muscle Research and Mitochondrial Function, Cellex-IDIBAPS, Faculty of Medicine, University of Barcelona, Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain CIBERER, Valencia, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Garrabou
authors.affiliation: Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Casademont
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Avda Diagonal 643, Barcelona 08028, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Giralt
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Avda Diagonal 643, Barcelona 08028, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000502:physiology; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D000099156:Superoxide Dismutase 2
chemical_list: D005346:Fibroblast Growth Factors; D007473:Ion Channels; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D000099156:Superoxide Dismutase 2; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; C000604390:Ucp2 protein, mouse; C000604393:Ucp3 protein, mouse; C414620:fibroblast growth factor 21
keywords: Cardiac disease; Fgf21; Oxidative stress; ROS