Heart disease is the leading cause of death in the United States, and yet treatments remain remarkably limited. Aside from statins to lower cholesterol levels, most interventions are indirect, such as preventing diabetes and high blood pressure or improving diet and exercise.
A new study led by the University of Michigan reveals that an immunological protein may be a major contributor to atherosclerosis, or the hardening of arteries in the heart. And this discovery opens the door to a new generation of medicines aimed at a disorder that affects practically every individual as they age.
“Targeting the immune component central to the development of atherosclerosis is the Holy Grail for the treatment of heart disease,” explained Salim Hayek, senior author of the new study “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.”
What is suPAR?
The latest study concentrated on an immunological protein known as suPAR (soluble urokinase plasminogen activator receptor). The protein is generated by bone marrow and acts as a general immune system modulator.
SuPAR has long been recognized as an effective immune activity biomarker by researchers. High levels of suPAR have been related to everything from cancer to diabetes but most recently the immune protein has been revealed to play a causative role in kidney disease. Preclinical investigations have indicated blocking suPAR can prevent, or even reverse, kidney injury, indicating the protein may be more pathogenically connected to disease than previously assumed.
This new study used three distinct ways to investigate the possibility of suPAR being a causative factor in cardiovascular disease. First, the researchers examined a 5,000-person cohort from an ongoing atherosclerosis investigation. Higher suPAR levels were shown to be substantially associated with higher rates of cardiovascular events in this study.
The researchers then looked for any relevant genetic variations that could alter suPAR levels. Using a dataset of 24,000 people, the researchers discovered that a specific mutation in a gene called PLAUR could be associated with greater blood suPAR levels. Following that gene mutation in 500,000 people, the researchers discovered it may be connected to a greater incidence of atherosclerosis.
“We also found that participants lacking a copy of the PLAUR gene have lower risk of heart disease,” said George Hindy, first author of the study. “Altogether, the genetic data is truly compelling for high suPAR being a cause of atherosclerosis.”
Figuring out how suPAR could be contributing to the development of atherosclerosis was the final piece of the puzzle. The researchers overexpressed suPAR levels in mice models of atherosclerosis. Plaques in the arteries of the animals were found to be much higher than suPAR levels. Co-first author Daniel Tyrrell also noted that suPAR appeared to promote arterial calcification.
“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,” Tyrrell explained. “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.’”
Finally, these unexpected discoveries lead to a completely different approach to treating cardiac disease. Inhibiting suPAR could theoretically lessen one’s risk of cardiovascular disease and there are medicines already in development seeking to accomplish exactly that.
In preclinical investigations focusing on kidney illness, monoclonal antibodies and small molecule inhibitors targeting suPAR have shown promising outcomes. In addition, plasmapheresis, a blood treatment technique, has been shown to both reduce suPAR levels and stabilize severe renal disease in human patients.
Hayek stated that finding ways to safely reduce suPAR levels will be critical, but he and his colleagues are already working on devising tailored medicines.
“My hope is that we are able to provide these treatments to our patients within the next three to five years,” he said. “This will be a game changer for the treatment of atherosclerotic and kidney disease”.
Source study: The Journal of Clinical Investigation— Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis