“Combining research and clinical training allows you to fundamentally advance our knowledge of human diseases,” Dr. Khetarpal explained. In his research, he studies the heart both as the primary organ of the circulatory system, but also as an important member of the endocrine system, regulating the body’s functions by releasing signaling molecules and hormones. These cardiac signals are modulated by exercise and illness. Natriuretic peptides, for example, are proteins released by the heart when it stretches or experiences increased pressure. They beneficially regulate blood pressure, and a common drug prescribed in heart failure, sacubitril-valsartan, in part prevents them from being broken down. “Since the discovery and targeting of natriuretic peptides for heart disease, we haven’t found many other heart-secreted proteins. I think there’s an opportunity to be inspired by this successful example and use new tools to identify other heart-derived proteins that can benefit patients,” says Dr. Khetarpal.

In his new paper, Dr. Khetarpal identifies a particular receptor in heart muscle cells, PGC-1α, essential for the heart to benefit from endurance exercise. Typically, exercise helps heart cells grow and function more efficiently. However, when Dr. Khetarpal deleted PGC-1α from those same cells, exercise no longer had any benefit. In fact, mice without PGC-1α suffered heart failure within 6 weeks of starting endurance training. With extensive work, Dr. Khetarpal showed that PGC-1α prevents the heart from releasing GDF15, a cardiac signaling molecule, and that a surplus of GDF15 led to the harmful consequences he observed. Further research will explore the roles of PGC-1α and GDF15 in heart failure and the heart’s ability to adapt to adapt to exercise. 

Dr. Khetarpal is particularly interested to join the cardiovascular research community at UVA. Six years ago, he interviewed with Dr. Gary Owens, director of the CVRC, when he was considering where to do his Fellowship training. The conversations he had during that time resonated strongly enough to draw him back for his independent career. “There is a widespread spirit of inclusivity, collaboration, and altruistic mentorship for young scientists in the Cardiology Division. It really makes me feel like this is the right place,” he said.

This support from UVA will be bolstered by the network provided by the NIH K08 and Burroughs Wellcome Fund awards, which both provide five years of funding for physician scientists transitioning from training into faculty positions. Dr. Khetarpal was one of only thirteen recipients of the Burroughs Wellcome Fund award this year. In addition to financial support, he will have access to intellectual resources in the form of guidance, mentorship, and collaboration with other award recipients. The Career Award for Medical Scientists funds all areas of medical research, facilitating contacts between researchers who might not otherwise interact.

Dr. Khetarpal’s research team is currently hiring at the postdoctoral, graduate/MSTP, and undergraduate academic levels.  His lab also has available research specialist positions. Individuals interested in joining the lab should contact Dr. Khetarpal via email, available on his lab website.

Blood vessels are made of concentric layers. Closest to the bloodstream is a layer of endothelial cells, which functions as an internal “skin”, separating flowing blood from the rest of the vessel. These cells become dysfunctional in obesity, contributing to a range of complications. Adjacent to this skin-like layer are smooth muscle cells, which control blood flow and pressure by contracting and relaxing. “When we think about inflammation, we typically focus on immune cells releasing inflammatory signals that affect endothelial or smooth muscle cells,” explains Sonkusare. “We asked a different question: ‘Can endothelial and smooth muscle cells themselves release inflammatory signals that elevate blood pressure?’”

Under healthy conditions, communication between the neighboring endothelial and smooth muscle cells helps maintain a normal blood pressure. Sonkusare’s team hypothesized that this cellular crosstalk becomes disrupted—or even harmful—in obesity. To study the cellular dynamics at play, the Sonkusare Lab fed mice a high-fat diet to develop obesity. They then isolated single cells from small blood vessels of these mice to analyze the inflammatory signals they released. Comparing these samples to those from mice fed a normal diet allowed the lab to identify obesity-dependent changes in inflammatory cell signaling. “We found that in obese mice, smooth muscle cells release the inflammatory molecule TNF, which acts on neighboring endothelial cells,” said Maniselvan Kuppusamy, PhD, first author of the study. Notably, this process occurs only in small arteries that regulate blood pressure—not in large arteries like the aorta. Importantly, the same increase in smooth muscle-derived TNF was observed in small arteries from obese human patients.                

The study further reveals that TNF from smooth muscle cells disrupts a calcium transport protein in endothelial cells, which in turn impairs the blood vessel’s ability to dilate, ultimately increasing blood pressure. Having identified this process, the team sought to disrupt it. The team started with two sets of genetically engineered mice: one set had smooth muscle cells incapable of producing TNF and another with endothelial cells unable to respond to TNF. In both cases, the obese mice showed improved vessel dilation and reduced blood pressure. The team then used a drug that blocks endothelial response to TNF, R7050, in obese mice without genetic modifications. R7050 successfully lowered their blood pressures. Finally, to confirm the clinical significance of their results, the Sonkusare Lab tested R7050 on blood vessels from UVA patients with and without obesity. The drug has beneficial effects in humans as well, opening new research avenues and potential therapies for patients with obesity-related hypertension.

The Sonkusare Lab is currently hiring at the Postdoctoral and Research Scientist levels. Interested parties should contact Sonkusare via email.

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.

Read more in UVA Health’s Making of Medicine blog.