A Key Heart-Repair Gene Has Been Discovered

Human Heart Inflammation Disease

A myocardial infarction, commonly known as a heart attack, occurs when the blood supply to a portion of the heart muscle is inadequate.

A crucial hormone for heart repair has been identified.

The University of Bologna’s researchers, who are part of an international study team, have discovered a key gene in the healing of cardiac damage after a heart attack. The research, which was published in the journal Nature Cardiovascular Research, suggests that a class of steroid hormones called glucocorticoids, which promote cell maturation after birth while inhibiting cell proliferation, may be partially to blame for the heart muscle’s inability to recover after a heart attack.

“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.”

One of the greatest causes of death on the planet is heart disease. This is partially due to the fact that cardiac tissue cannot regenerate like other bodily tissues. Heart muscle cells die during a myocardial infarction and are replaced with scar tissue that is unable to contract. If the damage is severe, heart failure, in which the heart is unable to pump enough blood to fulfill the body’s demands, may result. The result of this condition can potentially have a number of detrimental effects, including sudden cardiac death.

Since the newborn’s respiratory and circulatory systems undergo quick and significant modifications to enable the shift from intrauterine to extrauterine life, the absence of regeneration capacity of heart tissue is a persistent characteristic from birth onward. Cardiac muscle cells specifically become more specialized in the newborn heart; they cease to be able to divide and stop expanding 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, realized that exposing neonatal heart muscle cells to these hormones induced the cells to lose their proliferative capacity. Consequently, they analyzed 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. they are 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.

Reference: “Glucocorticoid receptor antagonization propels endogenous cardiomyocyte proliferation and cardiac regeneration” by Nicola Pianca, Francesca Sacchi, Kfir Baruch Umansky, Maila Chirivì, Luisa Iommarini, Silvia Da Pra, Valentina Papa, Chiara Bongiovanni, Carmen Miano, Francesca Pontis, Luca Braga, Riccardo Tassinari, Elvira Pantano, Rahul Shastry Patnala, Martina Mazzeschi, Giovanna Cenacchi, Anna Maria Porcelli, Mattia Lauriola, Carlo Ventura, Mauro Giacca, Roberto Rizzi, Eldad Tzahor, and Gabriele D’Uva, 23 June 2022, Nature Cardiovascular Research.
DOI: 10.1038/s44161-022-00090-0

The was funded by the European ERA-CVD.

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