A research team involving the universities of Jaén and Cádiz, the MEDINA Foundation, the Cádiz Institute for Biomedical Research and Innovation, and national and international partners has identified the gene Walras as a possible factor in why some heart diseases affect men more often than women. The researchers found, for the first time in human cells studied in vitro and in mouse models of different cardiomyopathies, that Walras was more active in males with heart-muscle disease and impaired heart function. The finding may open a route to developing future treatments, but the work remains preclinical.
Cardiovascular diseases do not affect the sexes equally. Men have a higher prevalence of these conditions and, in many cases, more severe disease progression. This difference has been associated with the protective role of female hormones such as oestrogen, but the specific biological mechanisms operating inside cardiomyocytes—the heart’s main cells—are not yet fully understood.
The researchers say Walras produces an RNA molecule associated with stress and cell death in the heart. In the models studied, higher levels of molecules produced by Walras shifted the response of heart cells under stress towards cell death in males. Female mice with cardiomyopathy had lower levels, which may help their cells withstand damage. The team also found that oestradiol reduced Walras activity, while testosterone increased it.
The researchers examined hearts from male and female mice with different forms of cardiomyopathy, comparing which molecules were more or less active. They then artificially raised Walras levels in heart cells from males and females. In males, this led to greater cellular stress, poorer energy function and a stronger tendency towards cell death.
The team also studied the equivalent molecule, AP002340.1, in human heart cells. It triggered similar processes, suggesting the mechanism observed in mice may have a counterpart in humans. It has not, however, been tested in patients.
The study, “Walras modulates sex-dependent endoplasmic reticulum stress in cardiomyopathy,” was published in *Frontiers in Physiology*. The authors identify Walras as a possible therapeutic target that could potentially be blocked or modulated to help heart cells survive. They say further research must establish whether blocking Walras has an effect in live animals, when and for how long treatment should be given, the appropriate dose, and its safety. Researchers must also confirm whether the pathway behaves similarly in models closer to human disease.
The work was carried out with the participation of the Carlos III Health Institute, the National Centre for Cardiovascular Research (CNIC) and CIBERFES in Madrid, as well as Aix-Marseille Université and Sorbonne Université. Funding came from the Regional Ministry of University, Industry, Energy and Innovation through an excellence project, and from the Ministry of Science, Innovation and Universities.