title: Fas receptor signaling inhibits glycogen synthase kinase 3 beta and induces cardiac hypertrophy following pressure overload.
abstract: Congestive heart failure is a leading cause of mortality in developed countries. Myocardial hypertrophy resulting from hypertension often precedes heart failure. Understanding the signaling underlying cardiac hypertrophy and failure is of major interest. Here, we identified Fas receptor activation, a classical death signal causing apoptosis via activation of the caspase cascade in many cell types, as a novel pathway mediating cardiomyocyte hypertrophy in vitro and in vivo. Fas activation by Fas ligand induced a hypertrophic response in cultured cardiomyocytes, which was dependent on the inactivation of glycogen synthase kinase 3 beta (GSK3 beta) by phosphorylation. In vivo, lpr (lymphoproliferative disease) mice lacking a functional Fas receptor demonstrated rapid-onset left ventricular dilatation and failure, absence of compensatory hypertrophy, and significantly increased mortality in response to pressure overload induction that was accompanied by a failure to inhibit GSK3 beta activity. In contrast, Fas ligand was dispensable for the development of pressure overload hypertrophy in vivo. In vitro, neonatal cardiomyocytes from lpr mice showed a completely abrogated or significantly blunted hypertrophic response after stimulation with Fas ligand or angiotensin II, respectively. These findings indicate that Fas receptor signaling inhibits GSK3 beta activity in cardiomyocytes and is required for compensation of pressure overload in vivo.
authors.affiliation: Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
authors.forename: Cornel
authors.initials: C
authors.lastname: Badorff
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ruetten
authors.forename: Sven
authors.initials: S
authors.lastname: Mueller
authors.forename: Meike
authors.initials: M
authors.lastname: Stahmer
authors.forename: Doris
authors.initials: D
authors.lastname: Gehring
authors.forename: Frank
authors.initials: F
authors.lastname: Jung
authors.forename: Christian
authors.initials: C
authors.lastname: Ihling
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D006332:Cardiomegaly / Q000209:etiology* / Q000503:physiopathology; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D051381:Rats; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D019014:fas Receptor; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3