More good news about aspirin’s
effects on cardiovascular disease

AMPK activation in macrophages
may reduce development of atherosclerosis

We see commercials every day that remind us that we have no idea when a heart attack or stroke will occur. Then, shortly after that reminder, there is a plug for aspirin. Cardiovascular disease has been a leading cause of death in developed countries for years, and we know aspirin can improve cardiovascular health, specifically through its ability to disrupt prostaglandin synthesis and reduce coagulation.

Recently, the labs led by Gregory Steinberg at McMaster University and Morgan Fullerton at the University of Ottawa, both in Canada, reported a new effect of aspirin. In the Journal of Lipid Research, the researchers reported that salicylate, an unacetylated form of aspirin, improves cholesterol levels by targeting AMP-activated protein kinase, or AMPK, in macrophages.

Macrophages are immune cells that play an important role in the plaque formation of atherosclerosis, which is the primary cause for heart attacks and strokes. Atherosclerosis is the buildup of cholesterol and fats in macrophages in the vasculature, which causes plaque formation on the artery walls. This disease often is known as a silent killer, because it shows no symptoms until the plaque buildup is severe enough to block blood flow and cause critical damage that even can lead to death.

Researchers already knew that AMPK has a role in lipid metabolism and that the activation of AMPK improves cholesterol levels. However, the mechanism and importance of AMPK in the macrophage was unknown, so the Steinberg and Fullerton labs decided to study the role of AMPK activation in macrophages loaded with cholesterol, which are known as foam cells.

To activate AMPK, they used direct activators that bind to AMPK, including salicylate, a byproduct of aspirin. Activation of AMPK with salicylate increased efflux of cholesterol from the macrophages to extracellular acceptors such as high-density lipoprotein. They also demonstrated that macrophages that are deficient of AMPK cannot load off cholesterol to extracellular acceptors, which in turn increases foam cell formation.

These findings indicate that AMPK activation is important for controlling the removal of cholesterol from macrophages and that it thereby decreases foam cell formation and progression of atherosclerosis. Most importantly, the study shows that salicylate-based medications like salsalate, a dimer of salicylate, would be great drug candidates.

According to Steinberg, the team already is testing salicylate-based drugs in preclinical animal models and humans. It will be critical to understand more about the role AMPK plays in the progression of atherosclerosis.

Fullerton emphasized: “AMPK is a kinase with more than three dozen targets. It will be important to identify the precise molecular pathway or pathways that are responsible for the effect that is caused by AMPK (activation).” New information about and a better understanding of the mechanism could lead to the development of new therapies or modifications to existing aspirin regimens.

Photo of Nicole Parker Nicole Parker joined the University of Maryland, Baltimore County, in the Meyeroff Scholarship Program in 2007. She earned a B.S. in biochemistry and molecular biology from UMBC and is currently completing her Ph.D. in biochemistry and molecular biology at the Johns Hopkins School of Public Health, where she studies the biological activity of the protein GDNF and its effect on the spermatogonial stem and progenitor cells.