Fibroblast growth factor 21 protects the heart from oxidative stress.
AIMS
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.


METHODS AND 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.


CONCLUSION
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.
['Planavila|Anna|A|', 'Redondo-Angulo|Ibon|I|', 'Ribas|Francesc|F|', 'Garrabou|Gloria|G|', 'Casademont|Jordi|J|', 'Giralt|Marta|M|', 'Villarroya|Francesc|F|']
D000818:Animals D019898:Autocrine Communication D002478:Cells, Cultured D004195:Disease Models, Animal D005346:Fibroblast Growth Factors D006321:Heart D006333:Heart Failure D006801:Humans D007473:Ion Channels D008070:Lipopolysaccharides D008297:Male D051379:Mice D018345:Mice, Knockout D024101:Mitochondrial Proteins D032383:Myocytes, Cardiac D018384:Oxidative Stress D017382:Reactive Oxygen Species D013482:Superoxide Dismutase D000071246:Uncoupling Protein 2 D000071247:Uncoupling Protein 3
Oxidative stress ROS Fgf21 Cardiac disease