Together, the three researchers will identify correlations between LOY and HFpEF severity, LOY-related changes at the cellular level, and whether mouse models can inform our understanding of the disease. Specifically, the team will investigate whether LOY increases the prevalence of fibrosis, the formation of scar tissue, in the heart. “The work will merge molecular biology and clinical cardiology, particularly cardiac MRI,” Walsh explains. The Walsh lab will provide expertise in LOY and molecular biology methods. Dr. Patel’s research specialization is in cardiac MRI, and Dr. Abuannadi is an expert in heart failure. Together, the trio hopes to identify the sex-specific mechanisms giving rise to HFpEF. Understanding these mechanisms will facilitate future work to develop treatments for HFpEF in men and women.

Walsh and his research team address a part of this question in their recent article, “Hematopoietic Loss of the Y Chromosome Activates Immune Checkpoints and Contributes to Impaired Senescent Cell Clearance and Renal Disease,” published in Science Translational Medicine. Having shown previously that LOY in immune cells leads to increased heart failure mortality, the team turned to other organs. The team, led by Yohei Arai, MD, PhD, a postdoctoral researcher in the Walsh lab, analyzed over 216,000 samples from the UK and determined that men with a high degree of Y chromosome loss were up to six times more likely to develop chronic kidney disease than those who had not lost their Y chromosomes. To understand why, Dr. Arai studied male mice with LOY. Like humans, these mice developed kidney failure as they aged and recovered poorly from kidney injuries, showing more scarring compared to their counterparts with an intact genome. “Interestingly, they also had more senescent cells—zombie-like cells that don’t grow, but secrete molecules that can promote tissue injury,” explains Walsh. When Dr. Arai treated the Y-less mice with drugs that target these zombie cells, the extra kidney damage the mice suffered from was reversed, suggesting that the senescent cells were an important part of the system.

Senescent cells are known to accumulate as we age because the body’s immune cells struggle to dispose of them as efficiently. It takes ten times longer for an old mouse to eliminate a senescent cell than a young mouse, for example. Dr. Arai suspected that male immune cells without Y chromosomes had a harder time eliminating these cells. His hypothesis was correct. When he compared immune cells with and without LOY, the ones with LOY were worse at destroying senescent cells. Looking deeper, Dr. Arai found that men and male mice who had lost their Y chromosomes send signals to immune cells that prevent them from killing dangerous cells. Blocking those signals restored normal function in both the kidneys and immune system.

Walsh and Dr. Arai hypothesize that LOY suppressing the immune system could explain why LOY is associated with a wide array of cancers in males—the body loses its ability to destroy tumors before they become established. Many tumors even use the same immune suppression molecules seen in this study to evade destruction, which could explain why men tend to respond better to cancer therapies that block those signals. Future work will continue to explore LOY, its consequences, and treatment options.

In this video, Kenneth Walsh, Berne Cardiovascular Research Institute, University of Virginia, talks about his research into clonal hematopoiesis as a driver of cardiovascular disease. Kenneth describes the mechanisms underlying the connection between somatic mutation-driven clonal hematopoiesis, how this process is studied and the potential implications of clonal hematopoiesis as a causal risk factor for cardiovascular disease.

About the author:

Kenneth Walsh heads The Walsh Lab at the University of Virginia the Berne Cardiovascular Research Institute. Research in the Walsh laboratory investigates the signaling- and transcriptional-regulatory mechanisms that control both normal and pathological tissue growth in the cardiovascular system. A new project in the laboratory investigates how acquired mutations in blood cells contribute to the development of cardiovascular disease. Somatic DNA mutations accumulate over time in many tissues, and this is a hallmark of the aging process. In particular, somatic mutations in preleukemic “driver” genes within hematopoietic stem cells can confer “fitness” advantages leading to the clonal amplification of these cells. This process is referred to as clonal hematopoiesis, and it is remarkably prevalent in the elderly population. A number of recent studies have associated advanced clonal hematopoiesis with increased mortality and elevated risk of cardiovascular disease and stroke. Using the epigenetic regulator Tet2 as a test case, investigations in our lab provided the first mechanistic framework in support of the hypothesis that these somatic mutations represent a new causal risk factor for cardiovascular disease. This line of investigation has provided support for a new paradigm of inflammation-mediated cardiovascular disease that is summarized in this by recent papers from the lab. For more information visit here.

Original publication:

Video originally published on BioTechniques, a journal and digital platform from the Future Science Group providing the life science research community with an invaluable resource to access latest methods, techniques and protocols.

View full video and article at the biomedicine website