Cardiac failure, a debilitating condition where the heart struggles to pump blood effectively, is a leading cause of death worldwide. It disproportionately affects men, and for years, researchers have been searching for clues to explain why.
A new study from researchers at the University of Virginia (UVA) revealed a potential link between heart failure and a common occurrence in aging men: the progressive loss of the Y chromosome from certain cells called mosaic loss of Y (mLOY) (1). Geneticist Kenneth Walsh and his team identified the Uty gene on the Y chromosome as critical for cardiac health, offering a potential target for novel therapies to prevent the heart scarring that leads to cardiac failure in men.
“Loss of the Y chromosome was first described in 1963 in men,” said Walsh. “It wasn't until 2014 that our colleague Lars Forsberg at Uppsala University was able to associate that with accelerated mortality in men. But the question always was, ‘is it just a biomarker of biological aging, or is it driving the disease processes that's leading to shortened lifespans?’”
Traditionally, scientists believed that the Y chromosome, which is primarily linked to sex determination, wasn't crucial for overall health. However, Walsh and his team previously discovered that mLOY in male mouse blood cells associates with cardiac fibrosis and heart failure (2).
To pinpoint the culprit behind cardiac failure in mice lacking the Y chromosome, they tested if this phenomenon resulted from the complete loss of the chromosome or a specific gene on it. The team looked for a gene, or group of genes, to explain the relationship between the disruption of the Y chromosome and macrophage function. Four protein-coding genes encoded on the Y chromosome are expressed in cardiac macrophages: Kdm5d, Ddx3y, Uty, and Eif2s3y.
Being a man is particularly deadly, and half of that death can be explained by the accelerated loss of the Y chromosome.
- Kenneth Walsh, University of Virginia
The team used CRISPR/Cas9 to disrupt each of these four genes individually, and only disruption of Uty led to cardiac symptoms in the mice. They then observed that macrophages without Uty became more profibrotic, meaning they were more likely to promote scarring. This scarring process ultimately led to heart failure in the affected mice.
Parker Wilson, a pathologist at the University of Pennsylvania who was not involved in the study, said, “It was really exciting that the Walsh group was able to develop some of these models that can really tease out the difference between Y chromosome loss and other kinds of aneuploidy — even some of the genes that are important players in the Y chromosome.”
Walsh and his team plan to continue studying this phenomenon, and they are collaborating with cardiologists at UVA to continue investigating mLOY in men and whether it is associated with other cardiac diseases.
“Being a man is particularly deadly, and half of that death can be explained by the accelerated loss of the Y chromosome. It's stunning that people haven't studied this, but we are excited to,” said Walsh.
References
- Horitani, K. et al. Disruption of the Uty epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure. Nat Cardiovasc Res 3, 343–355 (2024).
- Sano, S. et al. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Science 377, 292–297 (2022).
