New factor linked to heart failure

When the workload on the heart increases, the ventricular wall may thicken too, known as cardiac hypertrophy. This is an adaptive response that reduces pressure on the heart and maintains the activity of this vital organ. It is often a reversible process that does not cause serious effects on the structure or function of the heart, but if the factor causing cardiac overload becomes chronic, it can lead to pathological hypertrophy with more serious effects (dilatation of the ventricular cavities, alterations in cardiac function, heart failure, etc.).

People with diabetes — specially type 2 diabetes (DM2) — are at increased risk of developing heart failure due to the presence of prominent risk factors (high blood pressure, obesity, coronary heart disease, etc.).

Now, a study published in the journal Cellular and Molecular Life Sciences has identified a new factor linked to the development of pathological hypertrophy. The results of the study suggest that increasing the activity of the GADD45A protein could be a promising therapeutic strategy to slow the progression of this clinical 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 tumour 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 tumour suppressor in cancer development, as well as its involvement in the regulation of catabolic and anabolic metabolic pathways and in the prevention of inflammation, fibroris 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.
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