Atherosclerosis is a condition characterized by the hardening of the arteries and is the leading cause of cardiovascular disease and death. This condition has long been believed to be the result of a complex interaction between excess cholesterol and swelling in the heart and blood vessels. It kills tens of thousands of Americans annually.
Quietly hiding in our arterial walls are immune system cells called macrophages, whose main job is to ingest other cells or matter recognized as dangerous or unfamiliar. As a result of this, these cells consume other cells supplies of cholesterol, creating efficient ways to metabolize the overabundance of cholesterol and dispose of it.
Some macrophages fail to properly discard the extra cholesterol, allowing it to collect inside them as droplets of fat, providing them with the name: macrophage foam cells.
Foam macrophages create molecules that call on other immune cells and set molecules free, triggering certain genes to start an inflammatory response. It has long been assumed that atherosclerotic lesions, globs of fatty foam cells, assembled within arterial walls, were the damaging result of a connection between uncontrolled cholesterol build-up and inflammation.
Christopher Glass, MD, PhD, a professor in the Departments of Medicine and Cellular and Molecular Medicine and senior author of this study published in Cell, and his team wanted to know why the macrophages failed to do their job and how cholesterol build-up led to swelling. During their study using two mouse models that produced a vast amount of macrophage foam cells, the researchers discovered two surprising results that contradict previous investigations.
"The first is that foam cell formation suppressed activation of genes that promote inflammation. That's exactly the opposite of what we thought happened. Second, we identified a molecule that helps normal macrophages manage cholesterol balance. When it's in abundance, it turns on cellular pathways to get rid of cholesterol and turns off pathways for producing more cholesterol."
That particular molecule is desmosterol, the final predecessor in the creation of cholesterol, made and used by cells as a compositional element of their membranes. In atherosclerosis lesions, the regular function of desmosterol is paralyzed.
The finding that demostral has the ability to decrease macrophage cholesterol, gives researchers and drug developers a new target at diminishing the risk of atherosclerosis.
Glass pointed out that a synthetic model almost identical to desmosterol exists, suggesting an immediate test-case for new studies. Previously in the 1950s, a drug called triparanol was developed to treat heart disease by blocking cholesterol production and increasing desmosterol levels. It was discovered to cause severe side effects such as blindness from a rare form of cataracts, and pulled from the market.
"We've learned a lot in 50 years. Maybe there's a way now to create a new drug that mimics the cholesterol inhibition without the side effects."