An international research team led by scholars from the University of Bologna has identified a key gene in the repairing of damage to the heart after a heart attack. The study - published in the journal Nature Cardiovascular Research - shows that the heart muscle's inability to regenerate after a heart attack is allegedly due, at least in part, to a class of steroid hormones, glucocorticoids, pushing heart muscle cells to mature after birth, while blocking their proliferation.
“Our results show that glucocorticoids act as an important brake on cardiac regenerative capacity: their inhibition showed promising results in the repair of damaged cardiac tissue,” explains Gabriele D'Uva, professor at the Department of Experimental, Diagnostic and Specialty Medicine at the University of Bologna, who coordinated the study. “This is a particularly relevant discovery, which in the future could lead to effective treatments to improve the heart condition of heart attack patients.”
Heart disease is one of the leading causes of death worldwide. This is partly because heart tissue, unlike other body tissues, is unable to regenerate. During a myocardial infarction, heart muscle cells die and are replaced by scar tissue that can no longer contract. If the damage is extensive, it may develop into heart failure, a condition whereby the heart cannot pump enough blood to meet the body's needs. This condition can then lead to various debilitating outcomes, including sudden cardiac death.
The lack of regeneration capacity of cardiac tissue is a constant feature from birth onwards, as a result of the rapid and important changes undergone by the newborn's respiratory and vascular system to allow the transition from intrauterine to extrauterine life. Specifically, in the neonatal heart, cardiac muscle cells become further specialized: they lose the ability to replicate and continue to grow in size.
“In contrast to most tissues in our body, which renew themselves throughout life, the renewal of cardiac tissue in adulthood is extremely low, almost non-existent,” confirms professor D'Uva. “This is a consequence of both the very low rate of proliferation of cardiac muscle cells and the absence of a significant population of "stem cells" in this tissue: severe damage to the heart, induced for example by myocardial infarction, is therefore permanent.”
In order to find a way to reverse this regenerative inability of the heart, scientists focused on glucocorticoids: a class of hormones that play an important role in the development, metabolism and maintenance of homeostasis and in the management of stressful situations.
In preparation for birth, glucocorticoids are known to induce lung maturation. Researchers, however, realised that exposing neonatal heart muscle cells to these hormones induced the cells to lose their proliferative capacity. Consequently, they analysed cardiac tissue during the first week of postnatal life and found an increase in the amount of the glucocorticoid receptor (GR). This suggests that glucocorticoid activity increases in the immediate postnatal period.
This led to the hypothesis that glucocorticoids may be responsible for the maturation of cardiac muscle cells, to the detriment of their replicative and regenerative capacity: This idea has now been demonstrated in the animal model using sophisticated molecular biology techniques.
Deletion of the GR receptor resulted in reduced differentiation of cardiac muscle cells, i.e. their remaining in an immature state, which led to an increase in their division into new cardiac cells. Researchers also explained the molecular mechanism responsible for the replicative blockade by glucocorticoids due to a modulation of cellular energy metabolism.
“Deletion of the glucocorticoid receptor has been shown to increase the ability of heart muscle cells to replicate following myocardial infarction, promoting a process of heart regeneration within a few weeks,” confirms professor D'Uva. “Similar results have also been obtained through the administration of a GR receptor inhibitor drug already approved for clinical use in humans.”
The research team now aims to test potential synergistic effects with other pro-regenerative stimuli in order to come up with more effective strategies for heart regeneration - a result that could help millions of patients worldwide.
The study was published in the journal Nature Cardiovascular Research under the title “Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration”. The research was developed also thanks to European ERA-CVD funding and was coordinated by Gabriele D'Uva, professor at the Department of Experimental, Diagnostic and Specialty Medicine at the University of Bologna, with a significant contribution by researchers Nicola Pianca and Francesca Sacchi.
The groups led by Mattia Lauriola (Department of Experimental, Diagnostic and Specialty Medicine), Giovanna Cenacchi (Department of Biomedical and Neuromotor Sciences), Luisa Iommarini (Department of Pharmacy and Biotechnology), Anna Maria Porcelli (Department of Pharmacy and Biotechnology) and Carlo Ventura (Department of Experimental, Diagnostic and Specialty Medicine) from the University of Bologna also collaborated on the project. Further analyses were conducted in collaboration with the research groups of Eldad Tzahor (Weizmann Institute of Science, Israel) and Mauro Giacca (King's College, UK), in addition to the group of Roberto Rizzi (INGM, Italy).
Journal
Nature Cardiovascular Research
Article Title
Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration