Gadd45γ regulates cardiomyocyte death and post-myocardial infarction left ventricular remodelling

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Signaling

Background:

• Post-infarction remodeling involves altered mitogen-activated protein kinase (MAPK) signaling.
• Growth arrest and DNA-damage-inducible 45 (Gadd45) proteins modulate MAPK activity and are involved in DNA repair.
• The specific role of Gadd45 gamma (γ) in cardiac function after myocardial infarction (MI) remains largely unknown.

Purpose of the Study:

• To investigate the contribution of Gadd45γ to heart failure (HF) following MI.
• To elucidate the underlying mechanisms of Gadd45γ action in the context of cardiac injury.

Main Methods:

• Gadd45γ expression was analyzed in murine cardiomyocytes under simulated ischemia and in mouse hearts during MI.
• Adeno-associated viral vector (AAV9) was used to overexpress Gadd45γ in cardiomyocytes.
• Gadd45γ knockout mice were used to assess its role in ischemic injury resistance.
• Mechanisms involving receptor-interacting protein 1 (RIP1) and caspase-8 activation via p38 MAPK were investigated.

Main Results:

• Gadd45γ is upregulated in cardiomyocytes during ischemic conditions and MI.
• Gadd45γ overexpression led to cardiomyocyte apoptosis, fibrosis, left ventricular dysfunction, and HF.
• Gadd45γ deletion conferred resistance to ischemic injury by limiting cardiomyocyte apoptosis.
• Gadd45γ activates RIP1 and caspase-8 in a p38 MAPK-dependent pathway to induce cardiomyocyte death.

Conclusions:

• Gadd45γ accumulation post-MI promotes HF development and persistence through cardiomyocyte apoptosis.
• The p38 MAPK pathway is crucial for Gadd45γ-mediated cardiomyocyte death.
• Gadd45γ is identified as a potential therapeutic target for mitigating HF progression.