Atherosclerosis is a consequence of macrophage dysfunction. Macrophages are innate immune cells that help to remove excess cholesterol from blood vessel walls; cholesterol is primarily manufactured in the liver, and must travel through the bloodstream on LDL particles to reach the rest of the body. Macrophages help to retrieve unwanted cholesterol and return it to the bloodstream, attaching it to HDL particles for a return to the liver and excretion. This all works just fine in youth, but with age macrophages become inflammatory and dysfunctional, overwhelmed by cholesterol and the aged tissue environment, failing at their tasks and ultimately dying. This leads to growing fatty lesions in blood vessel walls, inflammatory macrophage graveyards that call in more immune cells to their deaths. Ultimately, one of these lesions ruptures, causing a heart attack or stroke. This kills more than a quarter of humanity.
Macrophages are large white blood cells that cruise through our body as a kind of clean-up crew, clearing hazardous debris. But in people with atherosclerosis - fatty deposits and inflammation in their blood vessels - macrophages can cause trouble. They eat excess fat inside artery walls, but that fat causes them to become foamy. And foamy macrophages tend to encourage inflammation in the arteries and sometimes bust apart plaques, freeing clots that can cause heart attack, stroke, or embolisms elsewhere in the body.
Changing how macrophages express a certain protein could prevent that kind of bad behavior. Researchers found that the protein, called TRPM2, is activated by inflammation. It signals macrophages to start eating fat. Since inflammation of the blood vessels is one of the primary causes of atherosclerosis, TRPM2 gets activated quite a bit. All that TRPM2 activation pushes macrophage activity, which leads to more foamy macrophages and potentially more inflamed arteries.
Researchers demonstrated one way to stop the cycle, at least in mice. They deleted TRPM2 from a type of lab mouse that tends to get atherosclerosis. Deleting that protein didn't seem to hurt the mice, and it prevented the macrophages from getting foamy. It also alleviated the animals' atherosclerosis. Researchers are now looking at whether increased TRPM2 expression in monocytes (circulating precursors of macrophages) in the blood correlates with severity of cardiovascular disease in humans.