title: Gadd45γ regulates cardiomyocyte death and post-myocardial infarction left ventricular remodelling.
abstract: OBJECTIVE
  Post-infarction remodelling is accompanied and influenced by perturbations in mitogen-activated protein kinase (MAPK) signalling. The growth arrest and DNA-damage-inducible 45 (Gadd45) proteins are small acidic proteins involved in DNA repair and modulation of MAPK activity. Little is known about the role of Gadd45 in the heart. Here, we explored the potential contribution of Gadd45 gamma (γ) isoform to the acute and late phase of heart failure (HF) after myocardial infarction (MI) and determined the mechanisms underlying Gadd45γ actions.
  
  
  RESULTS
  The Gadd45γ isoform is up-regulated in murine cardiomyocytes subjected to simulated ischaemia and in the mouse heart during MI. To mimic the situation observed during MI, we enhanced Gadd45γ content in cardiomyocytes with a single injection of an adeno-associated viral (AAV9) vector encoding Gadd45γ under the cTNT promoter. Gadd45γ overexpression induces cardiomyocyte apoptosis, fibrosis, left ventricular dysfunction, and HF. On the other hand, genetic deletion of Gadd45γ in knockout mice confers resistance to ischaemic injury, at least in part by limiting cardiomyocyte apoptosis. Mechanistically, Gadd45γ activates receptor-interacting protein 1 (RIP1) and caspase-8 in a p38 MAPK-dependent manner to promote cardiomyocyte death.
  
  
  CONCLUSIONS
  This work is the first to demonstrate that Gadd45γ accumulation during MI promotes the development and persistence of HF by inducing cardiomyocyte apoptosis in a p38 MAPK-dependent manner. We clearly identify Gadd45γ as a therapeutic target in the development of HF.
authors.affiliation: INSERM, UMR-1048, Institute of Metabolic and Cardiovascular Diseases, 1 Avenue Jean Poulhes, 31432 Toulouse, France University Paul Sabatier, CHU of Toulouse, 31432 Toulouse, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lucas
authors.affiliation: INSERM, UMR-1048, Institute of Metabolic and Cardiovascular Diseases, 1 Avenue Jean Poulhes, 31432 Toulouse, France University Paul Sabatier, CHU of Toulouse, 31432 Toulouse, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mialet-Perez
authors.affiliation: INSERM, UMR-1048, Institute of Metabolic and Cardiovascular Diseases, 1 Avenue Jean Poulhes, 31432 Toulouse, France University Paul Sabatier, CHU of Toulouse, 31432 Toulouse, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Daviaud
authors.affiliation: INSERM, UMR-1048, Institute of Metabolic and Cardiovascular Diseases, 1 Avenue Jean Poulhes, 31432 Toulouse, France University Paul Sabatier, CHU of Toulouse, 31432 Toulouse, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.affiliation: Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marber
authors.affiliation: INSERM, UMR-1048, Institute of Metabolic and Cardiovascular Diseases, 1 Avenue Jean Poulhes, 31432 Toulouse, France University Paul Sabatier, CHU of Toulouse, 31432 Toulouse, France pierre.sicard@inserm.fr sicard123@yahoo.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sicard
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D020257:Ventricular Remodeling; D000097642:GADD45 Proteins
chemical_list: D002352:Carrier Proteins; D053181:Caspase 8; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; C121373:Gadd45g protein, mouse; D000097642:GADD45 Proteins; C490620:Ralbp1 protein, mouse; C505526:Casp8 protein, mouse
keywords: Cardiomyocytes; Cell death; Cell signalling; Gadd45γ; Post-myocardial ischaemia remodelling