When Nettie Steven discovered the Y chromosome in 1905 while studying the mealworm Tenebrio molitor, she identified it as a sex-determining chromosome. As it turns out, the chromosome also has important functions beyond determining sex. According to a study published July 14 in Science, a lack of the Y chromosome in bone marrow cells causes heart failure.
The work was led by Lars Forsberg, a geneticist at Uppsala University in Sweden, and Kenneth Walsh of the University of Virginia. Their team zeroed in on mosaic loss of Y chromosome (mLOY), a condition where some of a male’s somatic cells, particularly white blood cells, lose the Y chromosome. This condition, which is heavily associated with tobacco smoking, affects more than 40 percent of 70-year-old men in the UK Biobank cohort and is associated with a long list of illnesses, including Alzheimer’s disease.
See “Vanishing Y Chromosomes”
In a previous study, Forsberg and his colleagues had found that the loss of the Y chromosome in men’s blood cells increases their chances of developing cancer and of dying from any cause, and in the new work, he and Walsh went on to explore how this loss affects the heart. Prior to the new report, a study had already established an association between the loss of the Y chromosome and cardiovascular diseases; the authors say they wanted to go a step further and find out whether the relationship is causal. The team knocked out the chromosome in mice’s bone marrow cells by deleting its centromere with CRISPR, mirroring the degeneration of the Y chromosome in male humans. The modification successfully induced blood chimerism—a condition where an individual has two sets of genetically different cells, in this case one with and one without the Y chromosome—in 81 percent of the mice. The researchers report that this scenario is consistent with the level of mosaic loss of Y chromosome (mLOY) in men that has been linked with Alzheimer’s disease. In the study, the team observed that these mice had a shorter lifespan than unmodified controls.
When the researchers looked at the hearts of mLOY mice using ultrasound, they noticed the development of cardiomyopathy—a chronic disease of the heart muscle—that worsened with age. Further analysis showed an increase in the quantity of fibroblasts (a cell that donates materials for wound healing) and more scar tissue—known as fibrosis—in the heart. The researchers suggest in their paper that rapid fibrosis could serve as a marker for heart dysfunctions caused by mLOY.
Only 40 percent of the mLOY mice survived to 19 months of age, compared to more than 50 percent of the controls. Overall, says Forsberg, the study demonstrates “that this is more than an association. There’s a causal effect from the loss of Y on the risk for cardiovascular disease.”
To see how their findings might apply to humans, the team analyzed survival data of more than 200,000 men in the UK Biobank. They found that during an average follow-up time of 11.5 years, men with loss of Y chromosome in more than 40 percent of their white blood cells showed a 31 percent increased risk of cardiovascular disorders like hypertensive heart disease compared with men without mLOY.
Joseph Hill, a cardiologist at UT Southwestern Medical Center who was not involved in the study, says the research team made an “intriguing analysis” that provides evidence of a mechanistic link among loss of the Y chromosome, aging, and heart disease.
Hill notes that fibrosis is a complicated condition. For instance, it is a welcome development during a heart attack, as it promotes healing, but poses a threat when it emerges from high blood pressure. “Fibrosis is multifaceted. It [can] cut both ways: There are situations in which you would not want to target fibrosis and there are others in which you would want to target fibrosis therapeutically. The authors are suggesting that this may be one particular example” where it would be beneficial to target fibrosis therapeutically, Hill explains.
“It’s certainly interesting and it fits well within the construct that fibrosis is driven by inflammation,” says Don Rockey of the Medical University of South Carolina who studies fibrosis but did not participate in the study. He says he’d be interested in knowing whether this phenomenon occurs in other organs like the liver or kidney. However, he adds that it’s unclear how the loss of the Y chromosome leads to inflammation in the heart.
Forsberg and his team also explored how the damage caused by a missing Y chromosome might be reversed. They treated the mLOY mice with an antibody targeting a protein called TGFβ1, which contributes to the spread of fibroblasts in the heart. The rate at which the fibroblasts proliferated in the mLOY mice’s hearts fell, thus reversing the heart dysfunction. “The immune cells with loss of Y in the heart . . . stimulate fibroblasts with this TGFβ1, thereby increasing fibrosis. What we saw in the mouse was that if we blocked the signaling pathway, the fibrosis disappeared,” Forsberg says. “This [of] course has to be studied carefully, but it works in mice, so it might work in humans as well.”