For the longest time, clinicians have treated cardiovascular disease by focusing on diabetes and blood pressure control, reducing cholesterol using medications like aspirin and statins.
Despite these measures, heart disease remains the number one cause of death in the United States, with many patients having heart attacks even after their risk factors are controlled.
In a study from the University of Michigan, scientists found a protein can cause atherosclerosis and kidney disease.
They uncovered a protein produced by the immune system that causes atherosclerosis – the hardening of arteries that affects over a billion people worldwide – which offers the promise of new treatments.
This protein, called soluble urokinase plasminogen activator receptor, or suPAR, is produced by the bone marrow. It acts as a regulator, essentially a thermostat for the activity of the immune system, or “immunostat”.
Past studies have shown suPAR to be a marker of cardiovascular disease. But this study is the first evidence showing that the protein actually causes atherosclerosis when at high levels.
In the study, the team analyzed data from over 5,000 people without known heart disease and found that those who had higher suPAR levels were much more prone to develop atherosclerosis and experience cardiovascular events, regardless of their underlying risk factors.
Then, the investigators did a genetic study of 24,000 people to find whether certain genetic variations affected levels of suPAR in blood.
They discovered a specific variant in the gene PLAUR that codes for suPAR, and people with that genetic variant tended to have higher suPAR levels.
Most importantly, that genetic variant was linked to atherosclerosis in a Mendelian randomization analysis of 500,000 participants in the UK Biobank, which was replicated in two other large data sets.
Altogether, the genetic data is truly compelling for high suPAR being a cause of atherosclerosis.
Finally, in mouse models with high suPAR levels, researchers saw a dramatic increase in atherosclerotic plaques of mouse aortas compared to mice with normal suPAR levels.
What is unique about this study is that it brings to light high-quality clinical, genetic and experimental data – all pointing to suPAR as a cause of atherosclerotic disease.
Now the team is looking into developing treatments to reduce suPAR levels safely as a strategy to prevent and treat heart disease, especially since traditional therapies for atherosclerosis have no impact on suPAR.
The study dovetails findings that suPAR is known to be a pathogenic factor that causes kidney disease, which impacts one in seven Americans.
People often experience the two conditions together: two-thirds of people with kidney disease are affected by cardiovascular disease, and over 40% of patients with cardiovascular disease have signs of kidney disease.
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The study was conducted by Salim Hayek et al and published in the Journal of Clinical Investigation.
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