P142Gadd45 gamma regulates cardiomyocytes death and post-myocardial infarction left ventricular remodeling

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Abstract

Background: Postinfarction remodeling is accompanied and influenced by perturbations in oxidative stress status and MAPK signaling. The Growth arrest and DNA-damage-inducible 45 (Gadd45) proteins are small acidic proteins involved in modulation of MAPK activities. Despite its relationship with p38 MAPK and intense interest in the cancer field, little is known about the role of Gadd45 in the heart. Our aim is to explore the potential contribution of Gadd45 gamma (γ) isoform to the acute and late phase of heart failure after myocardial infarction (MI).

Methods and results: MI was induced in wild-type (WT) versus Gadd45 γ (KO) littermates 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 less left ventricular dilatation and dysfunction than WT mice. The left ventricular dilatation and dysfunction, hypertrophy and fibrosis remained better in the KO mice throughout the study (4 weeks). Given the significant reduction in left ventricular function evident as early as 1 week post-MI, we examined the infarct size following a 24-hour coronary artery ligation and found it to be decreased in the KO mice. This decreased susceptibility to ischemic injury–induced apoptosis was also seen in cardiomyocytes isolated from the KO mice that were exposed to hypoxia. In addition, necroptosis activity pathway (RIP1-3; caspase 8) was reduced in the KO mice.

To mimic the Gadd45 γ overexpression observed during MI and to better understand its crucial role during cardiomyopathy development, we injected 3 10^11 of cTNT-Gadd45 γ AAV9 particles i.v. and studied the cardiac function, fibrosis and biological markers of cardiac dysfunction. Four weeks after the cTNT-Gadd45 γ AAV9 injection, we observed a decrease in the cardiac function and an increase in the heart dilatation compared to the GFP AAV9 injected control mice. A remodeling process is engaging with more fibrosis after 4 weeks and it is associated with p38 MAPK and necroptosis pathway activation.

Conclusion: Gadd45 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 and persistence of heart failure, particularly in the balance of the cell death process.

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