The study, led by researchers at the NYU Grossman School of Medicine, examined the processes involved in atherosclerosis, in which fatty deposits build up in blood vessels. This buildup can obstruct blood flow and lead to a heart attack or stroke when it hardens into plaques and triggers an inappropriate immune response.
The new study, which was published on June 8 in the journal Nature Cardiovascular Research, showed that plasma (the liquid component of blood) from individuals with atherosclerosis causes immune cells in the blood to produce an inflammatory signal that is often quite strong. Subsequent studies revealed that the drug saracatinib significantly reduced this inflammatory signal in diseased tissue and human blood samples by more than 90 percent.
“Our findings provide new insights into the inflammatory mechanisms of atherosclerosis and show for the first time that saracatinib may offer an effective treatment in cases where standard therapy in the form of statins has failed,” said study co-author Letizia Amadori. , PhD, a senior research fellow at NYU Langone Health.
Doctors prescribe statins to lower the levels of harmful fats in the blood, but research shows that even after the plaque build-up is reduced, many patients remain inflamed, leaving them at high risk of heart attack. According to the study authors, the reasons for this chronic immune response in patients are not fully understood, and anti-inflammatory treatments are sometimes ineffective in patient studies.
In the study, the team analyzed blood samples from 34 men and women with atherosclerotic cardiovascular disease (ASCVD), all of whom were taking statins, and compared them with samples from 24 healthy donors.
To start using saracatinib, the study authors examined 4,823 genes, including 277 that are already known to play a role in inflammation and the production of cytokines and other proteins that drive chronic immune responses.
According to Amadori, the team reasoned that if a particular drug could stop the production of all these molecules, it could calm the response.
Rather than trying to create a suitable drug from scratch, researchers turned to a list of drugs already approved or tested for other purposes. Specifically, they looked at data sets from the National Institutes of Health called the Integrated Network-Based Cell Signature Library, which contain hundreds of thousands of test results that indicate the effects of various molecules, signaling proteins, and genetic changes on human cells.
Because this search showed that saracatinib can change the expression of target genes, the process by which genes are turned on to make proteins, the authors tested it in human cells, diseased tissues, and animal models to see if it could actually slow down. or reverse the inflammation caused by ASCVD.
Among the findings, the results revealed that saracatinib blocks the activity of genes responsible for the production of inflammatory proteins such as interleukin-1 beta and interleukin-6, which support immune reactivity in ASCVD. Notably, an interleukin-1 beta inhibitor was shown to be effective in preventing heart attacks in a previous study. At the same time, the drug boosted genes that make proteins that help clear plaque deposits by removing fat from the arteries.
Further experiments in rabbits revealed that saracatinib reduced plaque-induced inflammation by about 97 percent compared to untreated animals. Meanwhile, mice using the same treatment had up to an 80 percent reduction in cells associated with inflammation in the plaques and a 48 to 70 percent reduction in plaque deposits, depending on the dose of the drug, Amadori says.
“Our reverse-engineering approach to finding new uses for old drugs could theoretically be used to uncover treatments for virtually any disease involving inflammation,” said senior study author Chiara Giannarelli, MD, PhD, adding, “Because these chemical materials have already been used. Tested for safety, this technique offers a rapid and cost-effective approach to drug development.
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