Heart disease, also known as cardiovascular disease, is the leading cause of death worldwide. It refers to a range of conditions that affect the heart and blood vessels, including coronary artery disease, heart failure, and arrhythmias.
Studies have identified suPAR as a protein that contributes to the development of atherosclerosis and kidney disease, offering new therapeutic opportunities.
Traditionally, clinicians have addressed the treatment of cardiovascular disease by utilizing drugs such as aspirin and statins to control diabetes, blood pressure, and lower cholesterol.
However, heart disease remains the leading cause of death in the United States. Even when risk factors are managed, many patients still experience heart attacks, says Salim Hayek, M.D., Ph.D., physician scientist and medical director. University of Michigan Health Frankel Cardiovascular Clinic.
But research led by Michigan Medicine has revealed a protein produced by the immune system that causes atherosclerosis, the hardening of the arteries that affects more than a billion people worldwide, and could lead to new treatments. Expected.
“Targeting the immune component central to the development of atherosclerosis is the holy grail in the treatment of heart disease. A requirement to become a promising therapeutic target for atherosclerosis.”
This protein, called soluble urokinase plasminogen activator receptor (suPAR), is produced by the bone marrow. It acts as a regulator, essentially a thermostat or “immunostat” for the activity of the immune system.
Previous studies have shown suPAR to be a marker of cardiovascular disease. But this study, published in the Journal of Clinical Investigation, is the first evidence that high levels of protein actually cause atherosclerosis.
Three findings
First, the research team analyzed a multi-ethnic study of atherosclerosis consisting of more than 5,000 people without known cardiovascular disease who had higher suPAR levels, regardless of potential risk. found that people were much more likely to develop atherosclerosis and experience cardiovascular events.
The researchers then conducted a genetic study of 24,000 people to see if specific genetic variants affected suPAR levels in the blood. They found a specific variant in the suPAR-encoding gene PLAUR, and people with that gene variant tended to have higher suPAR levels. Most importantly, in Mendel’s randomized analysis of 500,000 UK Biobank participants, the genetic variant was associated with atherosclerosis.
“We also found that participants lacking a copy of the PLAUR gene had a lower risk of heart disease,” said lead author and geneticist George Hindy, MD, Ph.D., Regeneron Genetics Center. “Together, the genetic data make it really convincing that high suPAR is the cause of atherosclerosis.”
Finally, mouse models with high suPAR levels showed a dramatic increase in atherosclerotic plaques in mouse aortas compared to mice with normal suPAR levels.
“Even before the onset of atherosclerosis, mouse aortas with high suPAR levels contained more inflammatory leukocytes, and immune cells circulating in the blood were in an activated state, or ‘attack mode.’ “It was there,” said Dr. Daniel Tyrrell. UM Health He is co-first author and investigator at the Frankel Cardiovascular Center. “High suPAR levels appear to activate immune cells and prime them to overreact to a high-cholesterol environment, allowing these cells to invade the vessel wall and accelerate the development of atherosclerosis.”
What’s unique about this study, says Hayek, is that it reveals high-quality clinical, genetic, and experimental data pointing to suPAR as a cause of atherosclerosis.
“Currently, we are investigating the development of therapies that safely reduce suPAR levels as a strategy for preventing and treating heart disease, especially since conventional therapies for atherosclerosis do not affect suPAR. he said.
suPAR Linking Kidney and Cardiovascular Disease
The study is consistent with findings that suPAR is a known etiologic agent that causes kidney disease, which affects 1 in 7 Americans. People often experience these two states simultaneously. Two-thirds of his patients with kidney disease are affected by cardiovascular disease, and more than 40% of patients with cardiovascular disease have symptoms of kidney disease.
“This paper places suPAR in the context of renal and cardiovascular disease, a common factor that causes both through this inappropriate and persistent activation of the immune system,” said co-author, Jochen Reiser, M.D., Ph.D., Dean of Medicine at Rush University and an expert in suPAR research. “This was pointed out in Mendelian randomized genetic analyzes conducted by the researchers, which show that high suPAR is also associated with kidney disease.”
For both conditions, suPAR has long been known as a biomarker of poor prognosis and disease progression. In a 2020 study, Hayek’s team found that suPAR can exacerbate acute kidney injury, and that blocking suPAR can prevent it. A recent study led by Hayek found that levels of the protein were higher in heart failure patients and predicted death in those patients.
Research into the role of suPAR in health and disease has advanced rapidly over the past decade. Hayek says that suPAR has great potential as a successful therapeutic target for cardiovascular and renal disease. His lab has already begun designing anti-suPAR therapies and planning clinical trials.
“We hope to be able to offer these treatments to patients within the next three to five years,” he said. “This will be a game changer in the treatment of atherosclerosis and kidney disease.”
See also: “Increased soluble urokinase plasminogen activator levels regulate monocyte function to promote atherosclerosis.” George Hindy, Daniel J. Tyrrell, Alexi Vasbinder, Changli Wei, Feriel Presswalla, Hui Wang, Pennelope Blakely, Ayse Bilge Ozel, Sarah Graham, Grace H. Holton, Joseph Dowsett, Akul C. Fahed, Kingsley-Michael Amadi, Grace K. Arne, Annika Tekmura, Anis Ismail, Christopher Launius , Nona Sotodenia, James S. Pankow, Reese Wegner Tollner, Christian Erikstrup, Ole Birger Pedersen, Karina Banacik, Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, DBDS Consortium President , Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, President of the Regeneron Genetics Center, Gunnar Engström, Olle Melander, Marju Orho-Melander, Lili Zhao, Venkatesh L. Murthy, David J. Pinsky, Cristen J. Willer, Susan R. Heckbert, Jochen Reiser, Daniel R. Goldstein, Karl C. Desch, Salim S. Hayek, 4 October 2022, Journal of Clinical Investigation.
DOI: 10.1172/JCI158788
This study was funded by the National Heart, Lung, and Blood Institute (NHLBI), the Michigan Institute of Clinical Health (MICHR), and the Gilead Scientific Research Fellowship Program in Cardiovascular Disease.
Hayek and the University of Michigan have applied for patents on the use of suPAR levels in the management of cardiovascular disease and the use of anti-suPAR therapy as a strategy for the prevention and treatment of atherosclerosis. Hayek and Reiser are members of the Scientific Advisory Board of Walden Biosciences, a company developing suPAR-targeted therapies in kidney disease. Hindy, Haas, Nielsen and Lotta will receive salaries, shares and stock options from Regeneron Pharmaceuticals, Inc. Eugen-Olsen is the co-founder, shareholder and chief scientific officer of Virogates and named inventor of suPAR-related patents.
