Research has identified suPAR as a protein that contributes to the development of atherosclerosis and kidney disease, offering new treatment opportunities.
Traditionally, doctors have approached the treatment of cardiovascular disease by controlling diabetes and blood pressure and using cholesterol-lowering drugs such as aspirin and statins.
Yet heart disease remains the leading cause of death in the United States. Even when risk factors are controlled, many patients still experience heart attacks, according to Salim Hayek, MD, a physician-scientist and medical director of the University of Michigan Health Frankel Cardiovascular Clinics.
But a study led by Michigan Medicine has discovered a protein produced by the immune system that causes atherosclerosis, the hardening of the arteries that affects more than a billion people worldwide, offering promise for new treatments.
“Targeting the immune component critical to the development of atherosclerosis is the Holy Grail for treating heart disease,” said Hayek, the study’s lead author. “This is the first time that a component of the immune system that meets all the requirements has been identified.” requirements to be a promising treatment target for atherosclerosis.”
This protein, called soluble urokinase plasminogen activator receptor, or suPAR, is produced by the bone marrow. It acts as a regulator, essentially a thermostat of immune system activity, or “immunostat.”
Previous studies have shown that suPAR is a marker of cardiovascular disease. But this study, published in the Journal of Clinical Investigation, is the first evidence to show that the protein actually causes atherosclerosis when found at high levels.
First, the research team looked at the Multi-Ethnic Atherosclerosis Study, consisting of more than 5,000 people with no known cardiovascular disease, and found that those with higher levels of suPAR were much more likely to develop atherosclerosis and experience cardiovascular events, regardless of its underlying risk. factors
The researchers then conducted a genetic study of 24,000 people to determine if certain genetic variations affected blood levels of suPAR. They discovered a specific variant in the PLAUR gene that codes for suPAR, and people with that gene variant tended to have higher levels of suPAR. Most importantly, that gene variant was linked to atherosclerosis in a Mendelian randomization analysis of 500,000 participants in the UK Biobank, which was replicated in two other large data sets.
“We also found that participants who lack one copy of the PLAUR gene have a lower risk of heart disease,” said first author and geneticist George Hindy, MD, Ph.D., of the Regeneron Genetics Center. “Taken together, the genetic data is really compelling that high suPAR is a cause of atherosclerosis.”
Finally, in mouse models with high suPAR levels, the researchers observed a dramatic increase in atherosclerotic plaques in the aortas of the mice compared to mice with normal suPAR levels.
“Even before developing atherosclerosis, mouse aortas with high suPAR levels contained more inflammatory white blood cells, and immune cells circulating in the blood were in an activated state, or ‘attack mode,'” said Daniel Tyrrell, Ph.D. . ., co-first author and investigator at the UM Health Frankel Cardiovascular Center. “It appears that high suPAR levels activate immune cells and prime them to overreact to the high cholesterol environment, causing these cells to enter the blood vessel wall and accelerate the development of atherosclerosis.” .
What is unique about this study, Hayek says, is that it brings to light high-quality clinical, genetic, and experimental data, all pointing to suPAR as a cause of atherosclerotic disease.
“Now, we are investigating the development of treatments to safely lower suPAR levels as a strategy to prevent and treat heart disease, especially since traditional atherosclerosis therapies have no impact on suPAR,” he said.
SuPAR Links Kidney and Cardiovascular Diseases
The study dovetails with findings that suPAR is known to be a pathogen causing kidney disease, which affects one in seven Americans. People often experience the two conditions together: two-thirds of people with kidney disease are affected by cardiovascular disease, and more than 40% of patients with cardiovascular disease have signs of kidney disease.
“This article positions suPAR as the link between 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, MD, Ph.D., chair of the Department of Medicine at Rush University and an expert on the suPAR study. “This is pointed out in the researchers’ Mendelian randomization genetic analysis, which shows that a high suPAR level is also associated with kidney disease.”
For both conditions, suPAR has long been known as a biomarker of poor outcome and disease progression. In a 2020 study, Hayek’s team found that suPAR can worsen acute kidney injury, and that blocking suPAR prevents it. A recent study led by Hayek found that protein levels are high in heart failure patients and predict the patients’ death.
Research on the role of suPAR in health and disease has advanced rapidly in the last 10 years. Hayek says that suPAR has great potential to be a successful treatment target for cardiovascular and renal diseases. His laboratory has already begun work on the design of anti-suPAR therapies and the planning of clinical trials.
“My hope is that we can provide these treatments to our patients within the next three to five years,” he said. “This will be a game changer for the treatment of atherosclerotic and kidney disease.”
Reference: “Increased levels of soluble urokinase plasminogen activator modulates monocyte function to promote atherosclerosis” by 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, Akl C. Fahed, Kingsley-Michael Amadi, Grace K. Erne, Annika Tekmulla, Anis Ismail, Christopher Launius, Nona Sotoodehnia, James S. Pankow, Lise Wegner Thørner, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik , Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, representing the DBDS Consortium, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, representing 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, and Salim S. Hayek, October 4, 2022, Clinical Research Journal.
The study was funded by the National Heart, Lung, and Blood Institute (NHLBI), the Michigan Health and Clinical Research Institute (MICHR), and the Gilead Sciences Research Program in Cardiovascular Diseases.
Hayek and the University of Michigan have filed patents for the use of suPAR levels in the treatment of cardiovascular disease and the use of anti-suPAR therapies as a strategy to prevent and treat atherosclerosis. Hayek and Reiser are members of the scientific advisory board of Walden Biosciences, a company that designs suPAR-targeted therapies in kidney disease. Hindy, Haas, Nielsen, and Lotta receive salary, shares, and stock options from Regeneron Pharmaceuticals, Inc. Eugen-Olsen is a co-founder, shareholder, and Chief Scientific Officer of Virogates and Designated Inventor of suPAR-related patents.
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