Researchers Discover New Immune Target for Heart Disease Treatment

A new study led by researchers at Michigan Medicine has found a protein produced by the immune system that causes atherosclerosis, which could result in promising new treatments, according to the authors.

Clinicians have long treated cardiovascular disease by focusing on diabetes and blood pressure control, using medications such as aspirin and statins to reduce cholesterol. Despite the efficacy of these approaches, heart disease is the number 1 cause of death in the United States, with many patients experiencing heart attacks even with controlled risk factors.

Researchers have now discovered a protein, called soluble urokinase plasminogen activator receptor (suPAR), which could be a promising alternative. The protein acts as a regulator for the activity of the immune system, which has long been considered a key approach for this treatment space. This research marks the first evidence showing that suPAR causes atherosclerosis when at high levels.

“Targeting the immune component central to the development of atherosclerosis is the Holy Grail for the treatment of heart disease,” said senior author Salim Hayek, MD, in a press release. “This is the first time that a component of the immune system is identified that meets all the requirements for being a promising treatment target for atherosclerosis.”

The study findings have 3 key parts. First, the research team analyzed the Multi-Ethnic Study of Atherosclerosis and found that individuals with higher suPAR levels were much more prone to develop atherosclerosis and experience cardiovascular events, regardless of their underlying risk factors.

Next, the investigators conducted a genetic study of 24,000 individuals to determine whether certain genetic variations affected levels of suPAR in the blood. They found a specific variant in the PLAUR gene that codes for suPAR, and participants with that genetic variant tended to have higher suPAR levels. Importantly, that genetic variant was associated with atherosclerosis in a Mendelian randomization analysis of 500,000 participants in the UK Biobank, which was replicated in 2 other large data sets.

“We also found that participants lacking a copy of the PLAUR gene have lower risk of heart disease,” said first author and geneticist George Hindy, MD, PhD, in the press release. “Altogether, the genetic data is truly compelling for high suPAR being a cause of atherosclerosis.”

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

“Even prior to developing atherosclerosis, the mouse aortas with high suPAR levels contained more inflammatory white blood cells, and the immune cells circulating in blood were in an activated state, or ‘attack mode,’” said co-first author Daniel Tyrrell, PhD, in the press release. “High suPAR levels appear to activate the 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.”

Interestingly, Hayek noted that this research highlighted high-quality clinical, genetic, and experimental data, all of which point to suPAR as a cause of atherosclerotic disease. Additionally, research has found that suPAR is a pathogenic factor that causes kidney disease, which impacts 1 in 7 Americans.

Patients often experience both conditions, with two-thirds of those with kidney disease also experiencing cardiovascular disease. Similarly, more than 40% of patients with cardiovascular disease have signs of kidney disease.

“This paper places suPAR as the link between kidney and cardiovascular disease; a common factor causing both through this inappropriate, persistent activation of the immune system,” said co-author Jochen Reiser, MD, PhD, in the press release. “This is pointed out in the Mendelian randomization genetic analysis done by the investigators, showing that high suPAR is also linked to kidney disease.”

suPAR has long been known to be a biomarker for poor outcomes and disease progression in both kidney disease and cardiovascular disease. A 2020 study found that suPAR can worsen acute kidney injury and that blocking suPAR prevents it. A more recent study also found that levels of protein are high in patients with heart failure and predict death for patients.

With this growing body of knowledge, suPAR has the potential to be a successful treatment target for both cardiovascular and kidney disease.

“My hope is that we are able to provide these treatments to our patients within the next 3 to 5 years,” Hayek said in the press release. “This will be a game changer for the treatment of atherosclerotic and kidney disease.”

REFERENCE

New immune target to treat cardiovascular disease discovered. News release. Michigan Medicine; December 15, 2022. Accessed January 4, 2023. https://labblog.uofmhealth.org/lab-report/new-immune-target-to-treat-cardiovascular-disease-discovered