Novel immune targets for the treatment of cardiovascular diseases

Clinicians have long focused on treating cardiovascular disease with diabetes and blood pressure control, using aspirin and statins to lower cholesterol
.

Despite these measures, heart disease remains the number one cause of death in the United States, and many patients experience heart attacks even after their risk factors are under control, said Dr.
Salim Hayek, medical director of the University of Michigan Health Frankl Cardiovascular Clinic, an internal medicine scientist
.

But a study led by Michigan Medical College found a protein produced by the immune system that causes atherosclerosis — arteriosclerosis that affects more than 1 billion people worldwide — that holds hope
for new treatments.

Hayek, senior author of the study, said: "The core immune component targeting the development of atherosclerosis is the holy grail of treating heart disease, and this is the first time that one component of the immune system has been found to meet all the requirements
for a promising therapeutic target for atherosclerosis.
"

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

Past studies have shown that suPAR is a hallmark
of cardiovascular disease.
But the study, published in the Journal of Clinical Investigations, is the first to demonstrate that when protein levels are too high, it does lead to atherosclerosis
.

A three-pronged discovery

First, the team analyzed a multiracial study of atherosclerosis, made up of more than 5,000 people with no known cardiovascular disease, and found that those with higher levels of suPAR were more likely to develop atherosclerosis and experience cardiovascular events, regardless of their underlying risk factors
.

The researchers then conducted genetic studies on 24,000 people to determine whether certain genetic variants affected levels
of suPAR in their blood.
They found a specific variant in the PLAUR gene encoding suPAR, and people with this gene variant tend to have higher levels
of suPAR.
On top of that, this genetic variant was associated with atherosclerosis in a Mendelian randomization analysis of 500,000 participants conducted by the UK Biobank, which was replicated
in two other large datasets.

"We also found that participants who lacked a copy of the PLAUR gene had a lower risk of heart disease," said
geneticist George Hindy, lead author of the Regeneron Genetics Center.
"All in all, the genetic data is really convincing and high suPAR is one of
the causes of atherosclerosis.
"

Finally, in a mouse model with high suPAR levels, the researchers found a significant increase
in atherosclerotic plaque in the aorta of mice compared to mice with normal suPAR levels.

"Even before atherosclerosis occurs, the aorta of mice with high suPAR levels contained more inflammatory white blood cells, and the immune cells circulating in the blood were activated, or 'attack mode,'" said Daniel Tyrell, Ph.
D.
, co-first author and researcher
at the University of Michigan Health Frankl Cardiovascular Center.
"High suPAR levels appear to activate immune cells, causing them to overrespond to the high cholesterol environment, causing these cells to enter the blood vessel wall and accelerate the development of
atherosclerosis.
"

Hayek said the study is unique in that it reveals high-quality clinical, genetic and experimental data — all of which point to suPAR as the cause
of atherosclerotic disease.

"Now, we are researching and developing treatments to safely reduce suPAR levels as a strategy to prevent and treat heart disease, especially since traditional therapies for atherosclerosis have no effect
on suPAR," he said.

suPAR has been linked to kidney and cardiovascular disease

The study dovetails with the finding that suPAR is a causative factor in kidney disease, which affects one in seven Americans
.
People often experience both at the same time: two-thirds of people with kidney disease are affected by cardiovascular disease, and more than 40% of people with cardiovascular disease have signs of
kidney disease.

"This paper argues that suPAR is a link between kidney and cardiovascular disease; This is a common factor that leads to both through this inappropriate, sustained activation of the immune system," said co-author Jochen Reiser, Ph.
D.
, chair of the Department of Medicine at Rush University and an expert on the suPAR study
.
"The researchers noted in Mendelian random genetic analysis that high suPAR is also associated
with kidney disease.
"

For both conditions, suPAR has long been considered a biomarker for poor prognosis and disease progression
.
In a 2020 study, Hayek's team found that suPAR can worsen acute kidney injury, and blocking suPAR can prevent this damage
.
A recent study led by Hayek found that higher levels of protein in patients with heart failure predicted death
.

Over the past 10 years, research on the role of suPAR in health and disease has advanced rapidly
.
Hayek said suPAR has great potential to be a successful therapeutic target for cardiovascular and kidney diseases
.
His lab has already begun designing anti-Supar therapies and plans to conduct clinical trials
.

"I hope we can make these treatments
available to patients in the next three to five years," he said.
"This will change the treatment
of atherosclerosis and kidney disease.
"

Journal Reference:

1. 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 Thø rner, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik, Sø ren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, Mary E.
   Haas, Jonas B.
   Nielsen, Luca A.
   Lotta, Gunnar Engströ m, 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.
   Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis.
   Journal of Clinical Investigation, 2022; 132 (24) DOI: 10.
   1172/JCI158788