Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor β1–neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure–associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

Although the Y chromosome is the smallest and contains few genes, its functions are not fully understood. It has been observed, however, that mosaic loss of the Y chromosome in blood cells frequently occurs with age, and this alteration is associated with various medical conditions. Sano et al. modeled this process in mice by reconstituting their bone marrow with cells lacking the Y chromosome (see the Perspective by Zeiher and Braun). The resulting mice were prone to fibrosis and decreased cardiac function, especially in the setting of pressure overload, but they benefited from treatment with a transforming growth factor β1–neutralizing antibody. Human patients with loss of chromosome Y in their blood were also at greater risk of cardiac pathology, supporting the clinical relevance of these findings. —YN

The Y chromosome has been long considered a “genetic wasteland,” and beyond biological sex determination, there is little understanding of its functional role. Nevertheless, mLOY in blood cells has been linked to increased risk for mortality, cardiovascular disease, and other age-related disorders. In human somatic cells, mLOY is the most commonly acquired mutation in the male’s genome. However, a relationship between mLOY and pathogenesis has not yet been established.

Using CRISPR-Cas9, Soichi Sano and colleagues developed a mouse model of hematopoietic mLOY by reconstituting their bone marrow with cells lacking the Y chromosome. Sano et al. discovered that these mice displayed increased mortality and were more prone to age-related cardiac fibrosis and decreased cardiac function.

According to the findings, bone marrow-derived mLOY macrophages that infiltrate the heart trigger high transforming growth factor β(TGF-β1) activity, which leads to fibroblast proliferation and accelerated cardiac tissue fibrosis. Treatment with a TGF-βneutralizing antibody was shown to ameliorate these harmful effects. What’s more, a prospective study in human patients showed that those with mLOY in blood were also at a greater risk for cardiovascular dysfunction and associated mortality, suggesting the potential clinical relevance of Sano et al.‘s findings in mice.

“Indeed, several unexpected links between the Y chromosome, immune system, and complex polygenic traits have been discovered, suggesting an influence of the Y chromosome on immune and inflammatory responses in men,” write Andreas Zeiher and Thomas Braun in a related Perspective. “The study of Sano et al. reinforces this view and uncovers a crucial function of the Y chromosome in maintaining a healthy innate immune system, but further research is required to elucidate the mechanisms.”

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