They identify a protein essential in the development and activity of the heart

Scientists have discovered a key mechanism for the cardiac conduction system.

His research has allowed the identification of the Dhx36 protein in an animal model as an essential regulator in the development and functioning of the heart. The work has revealed the role of the Dhx36 helicase in the regulation of cardiomyocyte differentiation and the development of the cardiac conduction system.

Specialists from the Rare Diseases Research Institute of the Carlos III Health Institute (ISCIII), the Network Biomedical Research Center (CIBER, dependent on the ISCIII), the National Center for Cardiovascular Research (CNIC), the University Pompeu Fabra (UPF) and the Severo Ochoa Molecular Biology Center (CBMSO, dependent on the CSIC and the Autonomous University of Madrid (UAM)), in Spain.

The study has been led by scientists Pablo Gómez del Arco (ISCIII), Pura Muñoz-Cánoves (Pompeu Fabra University and Altos Labs) and Juan Miguel Redondo (CBMSO), and represents an important advance in the understanding of the mechanisms that regulate the cardiac conduction system. In addition to Gómez del Arco and Redondo, other members of the Cardiovascular Diseases Area of ​​the CIBER have participated in the research, with the collaboration of the teams of Jose Luis de la Pompa and David Filgueras, of the CNIC, and the Health Research Institute (IIS). ) of the San Carlos Clinical Hospital.

“The Dhx36 protein modulates the gene networks that control the differentiation of cardiomyocytes by resolving G-quadruplex structures in the promoters of key genes of the cardiac conduction system,” explains Gómez del Arco.

This process is essential for the formation of specialized cells that make up the system that transmits and controls the electrical impulses of the heart. “Mice that lack Dhx36 in their cardiomyocytes, both in the embryonic and adult stages, develop serious cardiac problems, such as dilated cardiomyopathy and blockage of electrical impulse transmission between heart chambers, specifically between the atria and ventricles of the heart. heart,” adds Muñoz Cánoves.

The new study also offers valuable information on the genes and signaling pathways involved in the cellular differentiation of the heart and in the development of the system of specialized fibers that make up the Purkinje system, crucial for the synchronization of ventricular contraction.

Dhx36 is a helicase that resolves structures called G-quadruplexes in RNA and DNA. The researchers deleted this protein in mouse cardiomyocytes during embryonic development, which caused the accumulation of unresolved G-quadruplexes in key genes, blocking their transcription and affecting the normal development of cardiac tissue specialized in the generation and transmission of cardiac impulse.

Furthermore, deletion of Dhx36 in adult cardiomyocytes caused a type of cardiomyopathy characterized by dilation of cardiac chambers and thrombus formation in the left atrium, suggesting that this protein is essential for maintaining postnatal cardiac health: “These results suggest that Defects in Dhx36 could be related to some heart diseases with relevant clinical repercussions due to affectation of the electrical activity of the heart and the development of some forms of dilated cardiomyopathy,” says Redondo.

Micrograph of mouse cardiomyocytes grown in the laboratory. (Photo: NIH)

The researchers conclude that this study represents an important advance in our understanding of how transcriptional regulation influences cardiac function. These discoveries could open new avenues of research for the development of therapies against certain medical problems that affect the cardiac conduction system within the pathological range of heart failure.

The study is titled “The G4 Resolvase Dhx36 Modulates Cardiomyocyte Differentiation and Ventricular Conduction System Development.” And it has been published in the academic journal Nature Communications. (Source: ISCIII / CSIC)