Dr. Kenneth Walsh and his team discovered how loss of the Y chromosome causes changes in heart immune cells, making them more susceptible to scarring and heart failure.

Researchers at the School of Medicine have discovered a gene on the Y chromosome that contributes to an increased incidence of heart failure in men.

Male Y chromosome defects progress throughout life and are detected in approximately 40% of men aged 70 years. UVA’s Dr. Kenneth Walsh found in 2022 that this loss contributes to scarring of the heart muscle, which can lead to fatal heart failure. (This discovery was the first to directly link the loss of the Y chromosome to specific harms to men’s health. Loss of the Y chromosome has been implicated in diseases ranging from Alzheimer’s disease to cancer. (The idea of ​​this is becoming more and more common.)

In an important follow-up study, Walsh and his team discovered how the loss of the Y chromosome causes changes in heart immune cells, making them more susceptible to scarring and heart failure.

In addition, researchers found that by administering drugs to laboratory mice that target the fibrotic process that leads to heart scarring, they could reverse harmful cardiac changes, and this was observed in men. may lead to similar treatments.

“Our previous research has shown that deletions of the entire Y chromosome contribute to heart disease in men,” said Walsh, director of UVA’s Center for Blood and Vascular Biology. “This new study identifies a single gene on the Y chromosome that may be responsible for the disease-promoting effects of Y chromosome loss.”

Understanding heart failure in men

Unlike women, who have two X chromosomes, men have an X and a Y. For a long time, genes located on the Y chromosome were not thought to play an important role in disease. Scientists thought that sex hormones explain the differences in certain diseases between men and women. But Walsh’s groundbreaking research helped change that perception. The study also suggested an explanation for why heart failure is more common in men than women. (Cardiovascular diseases, including heart failure, are the leading cause of death worldwide.)

Loss of the Y chromosome occurs in only a small percentage of an affected male’s cells. As a result, a so-called “mosaic phenomenon” occurs in which genetically different cells occur within a single individual. Researchers do not fully understand why this partial loss of the Y chromosome occurs, but it occurs primarily in older men and in men who smoke compared to men who do not smoke.

To better understand the effects of Y chromosome loss, Walsh and his team examined the genes found on the Y chromosome to determine which are important for heart scarring. One gene they investigated was Uti, scientists have determined, helps control the behavioral instructions of immune cells called macrophages and monocytes.time Uti The genes were disrupted individually or through loss of the Y chromosome, causing changes in the immune cells of laboratory mice. Suddenly, the macrophages became much more “pro-fibrotic,” or prone to scarring. Scientists have found that this also promotes heart failure.

“Identification of a single gene on the Y chromosome provides information on new druggable targets for treating fibrotic diseases,” said UVA Department of Cardiovascular Medicine and Robert M. Byrne Center for Cardiovascular Research. Mr. Walsh said.

By giving mice specially designed monoclonal antibodies, Walsh and his team were able to prevent harmful changes in macrophages. This stopped harmful changes in the heart, suggesting that, with further research, this approach could lead to a way to treat or avoid heart failure and other fibrotic diseases in men lacking the Y chromosome.

“We are currently working with clinical colleagues in UVA’s cardiology department to assess whether loss of the Y chromosome in men is associated with greater scarring of the heart,” said Professor Walsh. Ta. “This study will provide a new avenue for understanding the causes of heart disease.”

Based on this discovery, Walsh and his team believe that a small group of genes on the Y chromosome may have a major impact on a variety of diseases. Their new study identifies a mechanism that may lead to this, and they hope that further research will provide a better understanding of the unknown causes of illness and death in men.

“This study provides further evidence of the utility of studying the genetics of mutations that are acquired after conception and accumulate throughout life,” said Walsh. “These mutations appear to be as important for health and longevity as mutations inherited from parents. The study of these age-related mutations represents a new field in human genetics. ”

Publication of survey results

The researchers published their findings in the scientific journal Nature Cardiovascular Research. The team includes Keita Horitani, Nicholas W. Chavkin, Yohei Arai, Wang Ying, Hayato Ogawa, Mitsu Yura, Megan A. Evans, Jesse Cochran, Mark C. Tell, Ariel H. Polizio, Miho Sano, and Miura. Emily Yura, Yuka Arai, Heather Dobiak, Arthur P. Arnold, Bradley D. Gelfand, Karen K. Hershi, Soichi Sano, Walsh. The scientists have no financial interest in this research.

This research was supported by National Institutes of Health grants AG073249, HL142650, and HL152174. National Aeronautics and Space Administration, Grant 80NSSC21K0549. UVA Medical Scientist Training Program, Grant T32GM007267. American Heart Association Grant 23CDA1054358; Research Activity Grants 21K20879 and 22K08162; Japan Heart Failure Society. Japanese Circulation Society. Japan Cardiovascular Research Foundation. Senshin Medical Research Foundation MSD Life Science Foundation. Novartis; Kondo Memorial Medical Foundation. and a Bayer Scholarship for Cardiovascular Research.

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