Key Protein Regulates Pathways in Cardiac Remodeling

A new study indicated that the multifaceted growth arrest and DNA damage inducible 45A (GADD45A) protein contributes to cardiac remodeling as evidenced by a mouse model with systemic deletion of Gadd45a.

“Aside its well-established tumor suppressor activity, recent studies point to additional roles for GADD45A, including the regulation of catabolic and anabolic pathways, or the prevention of inflammation, fibrosis, and oxidative stress in some tissues and organs,” wrote study researcher Adel Rostami, of the University of Barcelona, Barcelona, and colleagues in Cellular and Molecular Life Sciences. “However, little is known about its function in cardiac disease.”

To better understand the role of GADD45A, Rostami and colleagues studied mice with systemic deletion of Gadd45a and cardiac cells of human origin. They found that this deletion affected cardiac metabolism in several ways.

Gadd45a suppression led to cardiac fibrosis, inflammation, and apoptosis. According to the researchers, these changes were associated with “an hyperactivation of the pro-inflammatory and pro-fibrotic transcription factors activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3).”

“Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy and subsequent heart failure, these results suggest that promoting the activity of this protein might be a promising therapeutic strategy to slow down the progression of these deleterious diseases,” the researchers wrote.

Deletion of Gadd45a also resulted in substantial cardiac hypertrophy, which negatively impacted cardiac morphology and function in knockout mice, according to the researchers.

In contrast, GADD45A overexpression in human cells played a role in preventing inflammatory and fibrotic responses induced by tumor necrosis factor-α.

The researchers acknowledged that more research is needed to understand how GADD45A regulates all these processes, and that this study did not look at the role of GADD45A in female mice.