Human Heart Inflammation Disease

Breakthrough in heart disease: discovery of a new immune target

Heart disease, also known as cardiovascular disease, is one of the leading causes of death worldwide. It refers to a group of conditions that affect the heart and blood vessels, including coronary heart disease, heart failure, and arrhythmias.

Research has identified suPAR as a protein that contributes to the development of atherosclerosis and kidney disease, offering new treatment possibilities.

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

However, heart disease continues to be 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 Health Frankel Cardiovascular Clinics.

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

“Targeting the immune component central to the development of atherosclerosis is the holy grail for the treatment of heart disease,” said Hayek, lead author of the study. “This is the first time that a component of the immune system has been identified which meets all the 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 showing that the protein actually causes atherosclerosis when at high levels.

Three-pronged conclusions

First, the research team analyzed the Multiethnic Atherosclerosis Study, which includes more than 5,000 people with no known cardiovascular disease and found that those with higher suPAR levels were significantly more likely to develop atherosclerosis and suffer cardiovascular events, regardless of their underlying risk. factors.

Next, the researchers conducted a genetic study on 24,000 people to determine if certain genetic variations affected levels of suPAR in the blood. They discovered a specific variant of the PLAUR gene that codes for suPAR, and people with this genetic variant tended to have higher levels of suPAR. More importantly, this genetic variant was linked to atherosclerosis in a Mendelian randomisation analysis of 500,000 participants from the UK Biobank, which was replicated in two other large datasets.

“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 that elevated 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.

“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,'” said Daniel Tyrrell, Ph.D., co-first author and researcher at 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 disease

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 that blocking suPAR prevents it. A recent study led by Hayek found that protein levels are elevated in heart failure patients 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.”

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, 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, 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 Investigation Journal.
DOI: 10.1172/JCI158788

The study was funded by the National Heart, Lung, and Blood Institute (NHLBI), the Michigan Institute for Clinical & Health Research (MICHR), 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.

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