Heart disease breakthrough: discovery of a new immune target

Research has identified suPAR as a protein that contributes to atherosclerosis and kidney disease, providing new opportunities for treatment.

Traditionally, doctors have approached the treatment of cardiovascular disease by controlling diabetes and blood pressure, and using medications such as aspirin and statins to lower cholesterol.

However, heart disease is still the leading cause of death in the United States. Even when risk factors are managed, many patients still experience heart attacks, according to Salim Hayek, MD, physician, scientist and medical director of the University of Michigan Cardiovascular Clinics.

But a study led by Michigan Medicine has uncovered a protein produced by the immune system that causes hardening of the arteries — hardening of the arteries that affects more than 1 billion people worldwide — which holds promise for new treatments.

“Targeting the immune component essential to the development of atherosclerosis is the holy grail of treating heart disease,” said Hayek, senior author of the study. requirements of being a promising therapeutic target for atherosclerosis”.

This protein, called the soluble plasminogen activator receptor, or suPAR, is produced by the bone marrow. It acts as a regulator, essentially a thermostat for the activity of the immune system, or “immune system”.

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 hardening of the arteries when at high levels.

Triple results

First, the research team analyzed the Multiethnic Atherosclerosis Study, which consists of more than 5,000 people with no known cardiovascular disease, and found that those with higher levels of sopar were more likely to develop atherosclerosis and experience cardiovascular disease, regardless of Regardless of the risks behind them. Factors.

Next, the researchers conducted a genetic study of 24,000 people to see if certain genetic variations affected sopar levels in the blood. They discovered a specific variant in the PLAUR gene that codes for suPAR, and people with this genetic variant tend to have higher levels of suPAR. Importantly, this genetic variant was associated with atherosclerosis in a Mendelian randomization analysis of 500 000 UK Biobank participants, which was replicated in two other large datasets.

“We also found that participants who lack a copy of the PLAUR gene have a lower risk of heart disease,” said first author and geneticist George Hendy, MD, of the Regeneron Genetics Center. “All in all, the genetic data is really compelling that elevated suPAR is a causative agent of atherosclerosis.”

Finally, in mouse models with high levels of suPAR, the researchers observed a significant increase in atherosclerotic plaques in the mouse aorta compared to mice with normal levels of suPAR.

“Even before developing atherosclerosis, the aorta of a mouse with high levels of suPAR had more inflammatory white blood cells, and the immune cells circulating in the blood were in activated, or ‘attack mode,'” said Daniel Tyrrell, PhD. , co-author and research fellow at the UM Health Frankel Cardiovascular Center.”High levels of suPAR appear to activate immune cells and stimulate them to overreact to the elevated cholesterol environment, causing these cells to enter the blood vessel wall and accelerate the progression of atherosclerosis. “

What’s unique about this study, Hayek says, is that it highlights high-quality clinical, genetic and experimental data – all of which point to suPAR as a cause of atherosclerosis.

“Now, we look forward to developing therapies to safely reduce suPAR levels as a strategy for preventing and treating heart disease, especially since conventional treatments for atherosclerosis have no effect on suPAR,” he said.

suPAR that links renal and cardiovascular disease

The study matches findings that suPAR is known to be a pathogen that causes kidney disease, which affects one in seven Americans. People often have both conditions: two-thirds of people with kidney disease have cardiovascular disease, and more than 40% of patients with cardiovascular disease have signs of kidney disease.

This paper positions suPAR as a link between renal disease and cardiovascular disease; “A common factor causes both this inappropriate and persistent activation of the immune system,” said co-author Jochen Reiser, MD, chair of the department of medicine at Rush University and an expert on the SUPAR study. “This was indicated in the investigators’ Mendelian randomized genetic analysis, showing that elevated suPAR is also associated with kidney disease.”

For both conditions, suPAR has long been recognized 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 were elevated in heart failure patients and predicted patients’ death.

Research into the role of suPAR in health and disease has made rapid progress in the past ten years. Hayek says suPAR has great potential to be a successful therapeutic target for cardiovascular disease and kidney disease. His lab has already begun designing anti-suPAR therapies and planning clinical trials.

“I hope we can offer these therapies to our patients within the next three to five years,” he said. “This will be a game-changer in the treatment of atherosclerosis and kidney disease.”

Reference: “Increased levels of urokinase soluble plasminogen activator modulate monocyte function to promote atherosclerosis” by George Hendy, Daniel J. Terrell, Alexi Fassbender, Changli Wei, Viril Briswala, Hui Wang, Penelope Blakely, Ace Belge Ozel, Sarah Graham, and Grace e. Houlton, Joseph Dausset, Akl Si Fahad, Kingsley-Michael Amadi, Grace K. Ern, Anika Takmala, Anees Ismail, Christopher Launios, Nona Sotodehnia, James S Panko, Lise Wegner Thorner, Christian Erikstrup, Ole Berger Pedersen, Karina Banasek, Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, on behalf of the DBDS Consortium, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, on behalf of the Regeneron Genetics Center, Gunnar Engström, Olle Melander, Margo Urho-Melander , Lily Gao, Venkatesh L. Murthy, David G. Pinsky, Christine J. Wheeler, Susan R. Heckebert, Jochen Reiser, Daniel R. 2022, Journal of Clinical Investigation.
doi: 10.1172/JCI158788

The study was funded by the National Heart, Lung, and Blood Institute (NHLBI), the Michigan Institute for Clinical and Health Research (MICHR), and the Gilead Science Research Scholar Program in Cardiovascular Diseases.

Hayek and the University of Michigan have patents filed for the use of suPAR levels in the management of cardiovascular disease and the use of anti-suPAR therapies as a strategy for the prevention and treatment of atherosclerosis. Hayek and Reiser are on the scientific advisory board for Walden Biosciences, a company that creates suPAR-targeted therapies in kidney disease. Hindy, Haas, Nielsen, and Lotta receive salary, stock, and stock options from Regeneron Pharmaceuticals, Inc. Eugen-Olsen is a co-founder, shareholder and chief scientific officer of Virogates and the named inventor of suPAR-related patents.