Discovery of a new immune target to treat cardiovascular diseases

“We also found that participants lacking one copy of the PLAUR gene had a lower risk of heart disease,” said first author and geneticist George Hindy, MD, Ph.D., of the Regeneron Genetics Center. “Overall, the genetic data is really compelling because high suPAR is a cause of atherosclerosis.

Finally, in mouse models with high suPAR levels, the researchers found a dramatic increase in atherosclerotic plaques in mouse aortas compared to mice with normal suPAR levels.

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“Even before developing atherosclerosis, the aortas of mice with high levels of suPAR contained more inflammatory white blood cells, and circulating immune cells in the blood were in an activated state, or ‘attack mode,'” declared Daniel Tyrell, Ph.D., co-first author and researcher at the UM Health Frankel Cardiovascular Center. “High levels of suPAR appear to activate immune cells and cause them to overreact to the cholesterol-rich environment, causing these cells to enter the wall of blood vessels and accelerating the development of atherosclerosis.”

What’s unique about this study, Hayek says, is that it highlights high-quality clinical, genetic and experimental data — all pointing to suPAR as the cause of atherosclerotic disease.

“Now we are looking to develop treatments to safely lower suPAR levels as a strategy for preventing and treating heart disease, especially since traditional therapies for atherosclerosis have no impact on suPAR.” , did he declare.

suPAR linking kidney and cardiovascular diseases

The study agrees with findings that suPAR is known to be a pathogenic factor that causes 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 show signs of kidney disease.

“This article places suPAR as the link between kidney and cardiovascular disease; a common factor causing both by 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 in the study of suPAR. “This is underscored in the Mendelian randomization genetic analysis performed by the investigators, showing that elevated suPAR is also linked to 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 make acute kidney injury worse and blocking suPAR prevents it. A recent study by Hayek found that protein levels are high in patients with heart failure and predict patient death.

Research on the role of suPAR in health and disease has advanced rapidly over the past 10 years. Hayek says suPAR has great potential to be an effective therapeutic target for cardiovascular and kidney disease. His lab has already begun designing anti-suPAR therapies and planning clinical trials.

“I hope we can provide these treatments to our patients within three to five years,” he said. “It will be a game-changer for the treatment of atherosclerosis and kidney disease.”

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Other authors include Alexi Vasbinder, Ph.D., RN, Ayse Bilge Ozel, Ph.D., Sarah Graham, Ph.D., Grace H. Holton, Kingsley-Michael Amadi, Grace K. Erne, Annika Tekmulla, Anis Ismail, MD, Christopher Launius, Lili Zhao, Ph.D., Venkatesh L. Murthy, MD, Ph.D., David J. Pinksy, MD, Cristen Willer, Ph.D., Daniel R. Goldstein, MD, Karl C Desch, MD, all of the University of Michigan. Other authors listed in online publication.

The study was funded by the National Heart, Lung, and Blood Institute, the Michigan Institute for Clinical & Health Research (MICR), and the Gilead Sciences Research Scholar Program in Cardiovascular Disease.

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

Article quoted: “Clinical, Genetic, and Experimental Increased Levels of Soluble Urokinase Plasminogen Activator Receptors Promote Atherosclerosis”, The Journal of Clinical Investigation. DOI: 10.1172/JCI158788

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