Discovery of new protein with an important role in atherosclerosis

Atherosclerosis is the underlying condition that causes heart attacks and strokes. Researchers at Radboudumc in the Netherlands have discovered a protein that appears to play an important role in atherosclerosis. The protein is called Prosaposin, and its role in atherosclerosis was sofar unknown. "We identified Prosaposin as a new potential target for the treatment of atherosclerosis," they write in a publication in Science Translational Medicine.

Atherosclerosis is caused by cholesterol that builds up in the vessel wall and triggers chronic inflammation. It has been well established that cholesterol lowering drugs help to treat atherosclerosis. Recent research has shown that inhibiting inflammation can also help to prevent heart attacks and strokes. The challenge now is to find ways to inhibit inflammation specifically in atherosclerosis, without impeding the rest of the body's defenses that protect us against infections.

Increased metabolic rate

The cells primarily responsible for inflammation in atherosclerosis are macrophages. The inflammatory activation of these cells is an energy demanding process. The cells therefore have to increase their metabolic rate considerably. “Unraveling how they do this provides insight into how we can slow down the inflammatory activity and thereby reduce atherosclerosis”.

Switch off the power

An international team of researchers, led by Raphaël Duivenvoorden of the Radboudumc in the Netherlands, has investigated what happens when you “switch off the power” of 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 shrinked and the inflammation decreased”.

New protein discovered

This result sparked their interest in unraveling the molecular mechanism underlying this potent anti-inflammatory effect. Their analyzes consistently revealed an important role for a protein called Prosaposin. Its role in atherosclerosis was sofar unknown. “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. ”

Prosaposin and atherosclerosis in humans

To find out if Prosaposin also plays a role in atherosclerosis in humans, they investigated its expression in human atherosclerotic lesions. “We saw substantial expression of Prosaposin by macrophages in atherosclerotic plaques and this was related to their inflammatory activity. It confirms that Prosaposin plays a key role in atherosclerosis, and is a potential new therapeutic target for the treatment of atherosclerosis.”

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Publication in Science Translational Medicine: Prosaposin mediates inflammation in atherosclerosis - Mandy M. T. van Leent, Thijs J. Beldman, Yohana C. Toner, Marnix A. Lameijer, Nils Rother, Siroon Bekkering, Abraham J. P. Teunissen, Xianxiao Zhou, Roy van der Meel, Joost Malkus, Sheqouia A. Nauta, Emma D. Klein, Francois Fay, Brenda L. Sanchez-Gaytan, Carlos Pérez-Medina, Ewelina Kluza, Yu-Xiang Ye, Gregory Wojtkiewicz, Edward A. Fisher, Filip K. Swirski, Matthias Nahrendorf, Bin Zhang, Yang Li, Bowen Zhang, Leo A. B. Joosten, Gerard Pasterkamp, Arjan Boltjes, Zahi A. Fayad, Esther Lutgens,Mihai G. Netea, Niels P. Riksen, Willem J. M. Mulder, Raphaël Duivenvoorden.