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0237: Gadd45 γ promotes cardiac dysfunction by inducing necroptosis pathway in a mouse model of chronic myocardial infarction

By Alexandre Lucas, Jeanne Mialet-Perez, Luc Lorgis, Frank Lezoualc’H, Angelo Parini, Michael Marber and Pierre Sicard

Abstract

BackgroundPostinfarction remodeling is accompanied and influenced by perturbations in MAPK signaling. The Growth arrest and DNA-damage-inducible 45 (Gadd45) proteins are small acidic proteins involved in DNA repair and modulation of MAPK activities. Despite its relationship with p38 MAPK, little is known about the role of Gadd45 in the heart. Our aim is to explore the potential contribution of Gadd45 gamma (γ) on heart failure development after myocardial infarction (MI).Methods and resultsMI was induced in wild-type (WT) versus Gadd45 γ (KO) mice by left anterior descending coronary artery ligation. Pre-MI, WT, and KO hearts had comparable chamber dimensions and ventricular function, but as early as 1 week post-MI, KO mice had significantly better cardiac function than WT mice. The left ventricular dilatation, dysfunction and fibrosis remained better in the KO mice throughout the study (4 weeks). We examined the infarct size following a 24-hour MI and found it to be decreased in the KO mice. In addition, necroptosis activity pathway (RIP1; caspase 8) was reduced in the KO mice. To mimic the Gadd45 γ overexpression observed during MI, we injected 3 10^11 of cTNT-Gadd45 γ AAV9 particles i.v. and studied the cardiac function. Four weeks after the cTNT-Gadd45 γ AAV9 injection, we observed a decrease in the cardiac function compared to the GFP-AAV9 injected control mice. A remodeling process is engaging with more fibrosis. Gadd45 γ overexpression activated the necroptosis pathway through p38 MAPK.ConclusionGadd45 γ promotes ischemic injury, accentuates post-MI remodeling and left ventricular dysfunction, and increases the progression to heart failure. The lost of gadd45 γ confers resistance to ischemic injury, at least in part, via limiting necroptosis pathway through a p38 MAPK dependant mechanism. This work, demonstrate the importance of Gadd45 γ/p38 MAPK complex in the development of heart failure, particularly in the balance of the cell death process

Publisher: Elsevier Masson SAS.
Year: 2014
DOI identifier: 10.1016/S1878-6480(14)71378-3
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