GADD45A suppression contributes to cardiac remodeling by promoting inflammation, fibrosis and hypertrophy

Abstract

The growth arrest and DNA damage inducible 45A (GADD45A) is a multifaceted protein associated with stress signaling and cellular injury. 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. However, little is known about its function in cardiac disease. In this study, we aimed to evaluate the role of GADD45A in the heart by using mice with constitutive and systemic deletion of Gadd45a, and cardiac cells of human origin. Gadd45a suppression in knockout mice triggered cardiac fibrosis, inflammation, and apoptosis, and these changes correlated with an hyperactivation of the pro-inflammatory and pro-fibrotic transcription factors activator protein-1 (AP-1), nuclear factor-kB (NF-kB), and signal transducer and activator of transcription 3 (STAT3). Deletion of Gadd45a also resulted in substantial cardiac hypertrophy, which negatively impacted cardiac morphology and function in knockout mice. Consistent with this, GADD45A overexpression in human AC16 cardiomyocytes partially prevented the inflammatory and fibrotic responses induced by tumor necrosis factor-alfa (TNF-alfa). Overall, data presented in this study highlight an important role for GADD45A in the heart, since it may prevent inflammation, fibrosis, and apoptosis, and, by this means, preserve cardiac function and performance. 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.

This work was partly supported by the grants PID2021-122116OBI00 (M.V.-C. and X.P.), funded by MICIU/AEI/https://doi.org/10.13 039/501100011033 and “ERDF, A Way of Making Europe”, and the “Fundació La Marató de TV3” to M.V-C. CIBER in Diabetes and Associated Metabolic Diseases (CIBERDEM), CIBER of Rare Diseases (CIBERER), and CIBER in Cardiovascular Diseases (CIBERCV) are Carlos III Health Institute projects. Support was also received from the CERCA Programme/Generalitat, and from grants PI21/00084 (Carlos III Health Institute) and INNVAL21/24 (IDIVAL) to F.N.