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GADD45A identified as a protective protein against cardiac stress
When the heart works harder than usual, its ventricular walls can thicken in a process called cardiac hypertrophy. This is initially an adaptive response that helps the heart maintain output under increased load, but when the stress persists it can transition to pathological hypertrophy — a maladaptive state linked to fibrosis, inflammation, altered cardiac mechanics, ventricular dilation and ultimately heart failure. People with type 2 diabetes (T2D) are at higher risk of these complications because of common comorbidities such as hypertension, obesity and coronary artery disease.
New translational research led by teams at the University of Barcelona (UB), the Institute of Biomedicine of the UB (IBUB), Sant Joan de Déu Research Institute (IRSJD) and CIBERDEM highlights the protein GADD45A as an intrinsic brake on processes that drive pathological hypertrophy. The study, published in Cellular and Molecular Life Sciences, used mouse models and human cardiomyocyte cultures to map how GADD45A limits proinflammatory and profibrotic signaling and preserves cardiac structure and function.
Scientific background: what GADD45A does in the heart
GADD45A (growth arrest and DNA damage inducible 45A) is a stress-responsive protein previously implicated in DNA repair, cell cycle regulation and cancer suppression. Emerging evidence also links GADD45A to metabolic regulation and protection from tissue inflammation and fibrosis. The UB-led team investigated whether GADD45A performs a similar protective role in cardiac tissue and cardiomyocytes.
Pathological hypertrophy develops through multiple interacting mechanisms: chronic inflammation, excessive extracellular matrix deposition (fibrosis), mitochondrial dysfunction, calcium-handling dysregulation, altered cardiomyocyte metabolism, hypertrophic growth of cardiomyocytes and cell death. Among these, fibrosis and inflammation are especially critical because they degrade myocardial compliance and electrical stability and correlate strongly with adverse clinical outcomes.
Key experiments and discoveries
Using genetic deletion models in mice, the researchers found that absence of GADD45A produced clear cardiac pathology: increased interstitial fibrosis, elevated markers of inflammation, higher rates of cardiomyocyte apoptosis and measurable deterioration of cardiac morphology and function. Molecular profiling pointed to hyperactivation of several transcription factors that orchestrate inflammatory and fibrotic programs — notably AP-1 (activator protein-1), NF-κB (nuclear factor-κB) and STAT3 (signal transducer and activator of transcription 3).
Complementary cell-based experiments with human AC16 cardiomyocytes showed that overexpressing GADD45A partially blunted the inflammatory and profibrotic response triggered by tumor necrosis factor-alpha (TNF-α), a central cytokine in cardiac inflammation. These in vitro results support the in vivo observations and suggest that increasing GADD45A activity can directly reduce signaling through proinflammatory pathways linked to hypertrophy progression.
Mechanistic insights
- AP-1, NF-κB and STAT3 are transcription factors that respond to cellular stress and inflammatory cues; when overactivated they promote expression of cytokines and extracellular matrix proteins that drive fibrosis.
- GADD45A appears to temper these transcriptional programs, lowering the expression of genes that mediate inflammation, matrix deposition and apoptosis.
- In mouse hearts lacking GADD45A, unchecked activation of these pathways correlates with structural and functional decline, indicating a causal role for GADD45A loss in disease progression.
Professor Manuel Vázquez-Carrera notes that 'fibrosis correlates directly with disease progression and adverse clinical outcomes,' highlighting why interventions that reduce fibrotic signaling may preserve cardiac function. Associate Professor Xavier Palomer emphasizes that the collective data point to an important cardioprotective role for GADD45A, capable of preventing inflammation, fibrosis and cell death in stressed hearts.
Implications for therapy and future research
The study raises GADD45A as a promising molecular target for therapies aimed at halting or slowing pathological hypertrophy, particularly in populations at elevated risk such as people with T2D. Potential therapeutic approaches could include small molecules that enhance GADD45A expression or activity, gene therapy strategies to restore GADD45A levels in vulnerable myocardium, or upstream interventions that stabilize GADD45A signaling under metabolic stress.
However, translating these findings to the clinic requires caution and further work. Key next steps include validating GADD45A's protective effect in larger and more diverse animal models, assessing long-term safety of GADD45A modulation, and testing whether interventions that boost GADD45A can reverse established fibrosis or only prevent progression. Because GADD45A also influences cell cycle and DNA-damage pathways, careful evaluation of off-target and oncologic risks is essential.
Expert Insight
Dr. Elena Marconi, a cardiovascular researcher not involved in the study, comments: 'This research adds an important piece to our understanding of molecular checks that keep cardiac remodeling in balance. Targeting a nodal regulator like GADD45A is attractive because it modulates multiple downstream pathways — inflammation, fibrosis and apoptosis — rather than a single effector. The challenge will be to find strategies that enhance GADD45A's protective actions in the heart without perturbing its roles in other tissues.'
Conclusion
The UB-led study expands knowledge of how hearts respond to chronic stress and identifies GADD45A as a multifunctional protector that restrains inflammatory and fibrotic signaling linked to pathological hypertrophy. While clinical translation will require rigorous preclinical validation and safety assessment, targeting GADD45A-related pathways offers a novel direction for therapies designed to prevent heart failure, especially in patients with metabolic disease such as type 2 diabetes.
Source: scitechdaily
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