| First Author | Lucas A | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 108 |
| Issue | 2 | Pages | 254-67 |
| PubMed ID | 26370247 | Mgi Jnum | J:258517 |
| Mgi Id | MGI:6140400 | Doi | 10.1093/cvr/cvv219 |
| Citation | Lucas A, et al. (2015) Gadd45gamma regulates cardiomyocyte death and post-myocardial infarction left ventricular remodelling. Cardiovasc Res 108(2):254-67 |
| abstractText | AIMS: 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 (gamma) isoform to the acute and late phase of heart failure (HF) after myocardial infarction (MI) and determined the mechanisms underlying Gadd45gamma actions. METHODS AND RESULTS: The Gadd45gamma 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 Gadd45gamma content in cardiomyocytes with a single injection of an adeno-associated viral (AAV9) vector encoding Gadd45gamma under the cTNT promoter. Gadd45gamma overexpression induces cardiomyocyte apoptosis, fibrosis, left ventricular dysfunction, and HF. On the other hand, genetic deletion of Gadd45gamma in knockout mice confers resistance to ischaemic injury, at least in part by limiting cardiomyocyte apoptosis. Mechanistically, Gadd45gamma activates receptor-interacting protein 1 (RIP1) and caspase-8 in a p38 MAPK-dependent manner to promote cardiomyocyte death. CONCLUSION: This work is the first to demonstrate that Gadd45gamma accumulation during MI promotes the development and persistence of HF by inducing cardiomyocyte apoptosis in a p38 MAPK-dependent manner. We clearly identify Gadd45gamma as a therapeutic target in the development of HF. |
