Atherosclerosis refers to the buildup of fats, cholesterol, and other substances in and on artery walls, which can restrict blood flow. In the United States, atherosclerosis is the leading cause of illness and death. In 2016, coronary artery disease (atherosclerosis that affects the arteries supplying blood to the heart) and stroke (atherosclerosis affecting the arteries to the brain), caused almost 18 million deaths worldwide.

Eating a healthy diet, exercise, and lowering blood pressure can help decrease the risk of atherosclerosis. Recent research has also shown that inhibiting inflammation can help to prevent heart attacks and strokes. Researchers are searching for ways to inhibit inflammation in atherosclerosis, without impeding the rest of the body’s defenses that protect us against infections. Now, researchers at Radboud University Medical Center (Radboudumc) in the Netherlands report they have discovered a protein, prosaposin, that appears to play an important role in atherosclerosis.

Their findings are published in the journal Science Translational Medicine in a paper titled, “Prosaposin mediates inflammation in atherosclerosis.”

The cells behind inflammation in atherosclerosis are macrophages. “Unraveling how they do this provides insight into how we can slow down the inflammatory activity and thereby reduce atherosclerosis,” explained Raphaël Duivenvoorden of the Radboudumc, who led the study.

The researchers decided to flip the switch off in macrophages. The main metabolic switch is a protein complex called mTOR. Using nanotechnology, they were able to specifically turn off this switch in macrophages and investigate its effect on atherosclerosis in a mouse model. “We saw after only a single week of treatment that atherosclerotic lesions shrunk and the inflammation decreased.”

“Using myeloid cell–specific nanobiologics in apolipoprotein E–deficient (Apoe−/−) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages’ inflammatory activity,” wrote the researchers. “By investigating transcriptome modifications, we identified Psap, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling.”

During their discovery, they found the protein prosaposin played an important role. “In additional experiments, we found that prosaposin has an important effect on macrophage’s metabolism. We also observed less development of atherosclerosis and vessel wall inflammation in mice that cannot produce prosaposin.”

Their findings open a door of understanding into the development of atherosclerosis. The discovery of prosaposin as a potential therapeutic target may lead to the development of new therapeutics.

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