Scientists have uncovered the protective role of the protein GADD45A in guarding the heart from harmful stress responses.
When the heart is placed under greater strain, its ventricular wall can thicken, a process known as cardiac hypertrophy. This change is a natural adjustment that helps ease pressure on the heart and maintain its function. In many cases it can be reversed without lasting consequences, but if the strain continues over time, the condition may progress to pathological hypertrophy, which can cause more severe problems (dilatation of the ventricular cavities, changes in cardiac performance, heart failure, etc.).
Individuals with diabetes, particularly those with type 2 diabetes (DM2), face a higher risk of heart failure because of common contributing factors (high blood pressure, obesity, coronary heart disease, etc.).
A recent study published in Cellular and Molecular Life Sciences has revealed a new factor involved in the development of pathological hypertrophy. The findings indicate that boosting the activity of the GADD45A protein may offer a potential therapeutic approach to slow the advance of this damaging heart condition.
The study is led by Professor Manuel Vázquez-Carrera and Associate Professor Xavier Palomer, from the UB’s Faculty of Pharmacy and Food Sciences, the Institute of Biomedicine of the UB (IBUB) and the Sant Joan de Déu Research Institute (IRSJD), and the CIBER’s area of Diabetes and Associated Metabolic Diseases (CIBERDEM). The first author of the article is the expert Adel Rostami (UB-IBUB-IRSJD-CIBERDEM).
A factor with a prominent role in cardiac function
The GADD45A (growth arrest and DNA damage inducible 45A) protein is a multifunctional factor associated with stress signalling and cell damage. In this study, the team assessed the role of GADD45A in cardiac function using animal models and human cardiac cells.
The main mechanisms involved in pathological hypertrophy include inflammatory processes, fibrosis, mitochondrial dysfunction, dysregulation of calcium-handling proteins, metabolic alterations, cardiomyocyte hypertrophy, and cell death. Fibrosis and inflammation are key factors in the progression of this pathological cardiac hypertrophy and subsequent heart failure.
“Fibrosis, in particular, correlates directly with the development of the disease and with adverse clinical outcomes, and has a major impact on the clinical condition of the patient,” says Professor Manuel Vázquez-Carrera.
The results reveal that the lack of GADD45A factor in mice triggers cardiac fibrosis, inflammation, and apoptosis. These changes correlate with hyperactivation of the proinflammatory and profibrotic transcription factors AP-1 (activator protein-1), NF-κB (nuclear factor-κB), and STAT3 (signal transducer and activator of transcription 3).
According to the findings, deletion of GADD45A also caused substantial cardiac hypertrophy that negatively affected cardiac morphology and function in mice lacking this protein. Furthermore, overexpression of GADD45A in human AC16 cardiomyocytes partially prevented the inflammatory and fibrotic response induced by tumor necrosis factor-alpha (TNF-α).
“Taken together, the data presented in this study highlight an important role for GADD45A protein in the heart, as it may prevent inflammation, fibrosis and apoptosis and thus preserve cardiac function,” says Xavier Palomer.
This paper expands our knowledge of the action mechanisms of GADD45A in the body. To date, previous studies have identified the role as a tumor suppressor in cancer development, as well as its involvement in the regulation of catabolic and anabolic metabolic pathways and in the prevention of inflammation, fibrosis, and oxidative stress in some tissues and organs. Finally, some studies have indicated that the modulation of GADD45A could be a suitable therapeutic strategy to prevent obesity and diabetes.
Reference: “GADD45A suppression contributes to cardiac remodeling by promoting inflammation, fibrosis and hypertrophy” by Adel Rostami, Xavier Palomer, Javier Pizarro-Delgado, Lucía Peña, Mònica Zamora, Marta Montori-Grau, Emma Barroso, Brenda Valenzuela-Alcaraz, Fàtima Crispi, Jesús M. Salvador, Raquel García, María A. Hurlé, Francisco Nistal and Manuel Vázquez-Carrera, 30 April 2025, Cellular and Molecular Life Sciences.
DOI: 10.1007/s00018-025-05704-x
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1 Comment
Poor mice!