GADD45A suppression contributes to cardiac remodeling by promoting inflammation, fibrosis and hypertrophy.
Por:
Rostami A, Palomer X, Pizarro J, Peña L, MATIAS ZAMORA RODRÍGUEZ, Montori M, Barroso E, Valenzuela-Alcaraz BI, Crispi F, Salvador JM, García R, Hurlé MA, Nistal F and Vazquez M
Publicada:
30 abr 2025
Ahead of Print:
30 abr 2025
Resumen:
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-?B (NF-?B), 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-a (TNF-a). 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.
Filiaciones:
Rostami A:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
Palomer X:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
Pizarro J:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
Peña L:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
MATIAS ZAMORA RODRÍGUEZ:
BCNatal - Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, 08028, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, 08036, Spain
Montori M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
Barroso E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
Valenzuela-Alcaraz BI:
BCNatal - Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, 08028, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, 08036, Spain
Crispi F:
BCNatal - Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, 08028, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, 08036, Spain
Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Madrid, 28029, Spain
Salvador JM:
Department of Immunology and Oncology, National Center for Biotechnology/CSIC, Madrid, 28049, Spain
García R:
Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
Hurlé MA:
Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
Nistal F:
Servicio de Cirugía Cardiovascular, Departamento de Ciencias Médicas y Quirúrgicas, Facultad de Medicina, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain
Spanish Biomedical Research Center in Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III, Santander, Spain
Vazquez M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, España
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain
Green Submitted, Green Accepted, gold
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