The fatty acid that makes the heart work well after birth

At birth, the baby’s heart must begin to rapidly produce energy to initiate the heartbeat in the extrauterine environment. To do this, cardiomyocytes, myocardial contractile cells, need to activate mitochondria, ATP-generating organelles (adenosine triphosphate or adenosine triphosphate) that support the cell’s bioenergetic pathways. Although this process is essential for the survival of the organism, until now there was very little information about the signals that trigger the physiological adaptation of the heart after childbirth.

A study led by researchers from the National Center for Cardiovascular Research (CNIC) in Spain has revealed that milk intake is the essential signal for the neonatal heart to mature metabolically after birth, allowing the heart to function properly and ensuring postnatal survival.

Specifically, it is the omega-6 fatty acid g-linolenic acid (GLA), which is responsible for binding to the cell protein Retinoid X Receptor (RXR). RXR is a protein that acts as a nutritional sensor for lipids and vitamin A derivatives, altering gene expression and influencing such important biological functions as immunity, cell differentiation or metabolism. Once RXR detects GLA, it launches genetic programs that equip mitochondria, the cells’ powerhouses, with the proteins needed to begin consuming lipids, the main source of energy in the mature heart.

The results of this new study could have vast therapeutic repercussions in cardiovascular pathologies where there are mitochondrial and metabolic dysfunctions, as well as diseases related to alterations in maturational processes after birth, says Dr. Mercedes Ricote, head of the Nuclear Receptor Signaling Group. of the CNIC and leader of the investigation.

Research has shown, in a mouse model, that both the absence of RXR in the heart and the lack of the omega-6 fatty acid GLA in breast milk prevent mitochondria from producing energy properly, leading to failure severe heart disease that ends up causing death between 24 and 48 hours after birth.

“The need to maintain a constant and uninterrupted heartbeat means that the heart requires high energy inputs,” explains Dr. Mercedes Ricote. “To meet their energy needs, cardiac cells have very tight control of the cellular pathways that produce energy. However, any imbalance in these bioenergetic mechanisms can lead to the appearance of serious cardiovascular pathologies”.

For Dr. Ricote, the novelty of this work “also resides in the fact that it is the first time that it has been shown that, contrary to what was believed, RXR plays an essential role in cardiac muscle. This finding represents a very important conceptual advance in the scientific field of nuclear receptors”.

The research, whose main author is Dr. Ana Paredes, proposes a very novel angle to understand the postnatal adaptations that are triggered for the organism to meet the requirements in the extrauterine environment. “Birth is a physiological challenge for the newborn,” says Dr. Paredes. “With this work we demonstrate that milk intake, in addition to its nutritional function, plays a signaling role, warning cardiomyocytes that they should activate their metabolism, because maternal physiology no longer supports them.”

The research, which stands out for its multidisciplinary perspective and combination of state-of-the-art massive sequencing techniques, has had the collaboration of the CNIC teams led by Dr. José Antonio Enríquez, Dr. Fátima Sánchez-Cabo and Dr. Jesús Vázquez .

In addition, several national and international centers have intervened. On the Spanish side: the National Center for Biotechnology and the Center for Biological Research Margarita Salas, both belonging to the Higher Council for Scientific Research (CSIC); the Complutense University of Madrid (UCM); the University of Barcelona (UB); the Institute of Functional Biology and Genomics / University of Salamanca (IBFG/USAL); the CEMBIO/CEU San Pablo; and the Network Biomedical Research Center for Cardiovascular Diseases (CIBERCV). On the Swedish side, the Karolinska Institute has collaborated.

In conclusion, the researchers note, the study shows that g-linolenic fatty acid (GLA) is the key signal for the heart to function properly after birth. GLA activates the cellular protein Retinoid X Receptor (RXR), and as a result, mitochondria mature for cardiomyocytes to produce energy in the extrauterine environment.

(Images: CNIC)

The results, the researchers emphasize, open up the possibility of modulating RXR activity in cardiac cells through the use of specific drugs, some of them approved by the US health authorities (FDA) for the treatment of some cancers. “Our work proposes RXR as a potential therapeutic target in neonatal heart diseases, and in systemic pathologies caused by metabolic failures”, concludes Dr. Ricote.

The study is titled “γ-linolenic acid in maternal milk drives cardiac metabolic maturation”. And it has been published in the academic journal Nature. (Source: CNIC)