Purging Plaques

Abstract

After you wash down a delectable cream-filled doughnut with a swig of cappuccino, cells in your arteries could also start gorging on fat, setting the stage for atherosclerosis. A new study suggests that coaxing these plaque-spawning cells to spit out their excess cholesterol might prevent heart disease. The discovery could lead to the development of drugs that thwart atherosclerosis by blocking the first step in plaque formation. Best known for slurping up bacteria, immune cells called macrophages also eat cholesterol, helping govern its concentration in the blood. Atherosclerosis starts when macrophages binge. The cells slip into the wall of an artery, perhaps drawn by an injury. Once ensconced in the vessel, they fill up on cholesterol, triggering the growth of fatty deposits on the vessel walls that can eventually reduce or block blood flow. Proteins called liver X receptors (LXRs) spur the liver to break down cholesterol; they also stimulate macrophages to eject cholesterol, allowing it to be spirited away for destruction. Because LXRs drive down blood cholesterol levels, drugs that stimulate the receptors might halt or reverse atherosclerosis. In May, molecular biologist Peter Tontonoz of the University of California, Los Angeles, and colleagues showed that tickling the receptors with a synthetic compound reduced plaque buildup in mice by more than one-third. However, several studies have found that such treatments also boost levels of blood triglycerides--which hike the risk of heart disease--probably through LXRs' actions in the liver or intestines. Tontonoz teamed with molecular biologist Rajendra Tangirala of X-Ceptor Therapeutics in San Diego, California, and colleagues to see whether stimulating LXRs only in macrophages could avert this side effect. The researchers irradiated atherosclerosis-prone mice to destroy their white blood cells and then gave the animals a new set of macrophages by means of a bone-marrow transplant. The rodents received marrow either from normal mice whose macrophages carry working LXRs or from mice that lack receptors. The mice injected with marrow that carries functional receptors showed 80% less plaque in their aortas without raising triglyceride values. The results suggest that LXR activity in macrophages hampers fatty buildup, probably by prodding the cells to dump their excess cholesterol, says Tangirala: "Clearly, there is a direct link between LXRs in macrophages and susceptibility to atherosclerosis." The study makes LXRs a prime target for artery-clearing drugs, says molecular biologist David Moore of Baylor College of Medicine in Houston, Texas. The results also raise the possibility that patients with high cholesterol levels might tote faulty versions of LXR, adds Steven Kliewer of the University of Texas Southwestern Medical Center in Dallas. But transforming the discovery into a treatment poses a huge challenge. Scientists will have to craft a drug that goads LXRs in macrophages without tweaking them in the liver or intestines. Nobody knows yet how to achieve that kind of selectivity. "Will it be difficult? Yes, but it's not impossible," says Moore. If the idea pans out, such drugs could spur macrophages to purge themselves of excess cholesterol and keep blood flowing, even if you can't resist eating the last doughnut in the box. --Mitch Leslie R. K. Tangirala, E. D. Bischoff, S. B. Joseph, B. L. Wagner, R. Walczak, B. A. Laffitte, C. L. Daige, D. Thomas, R. A. Heyman, D. J. Mangelsdorf, X. Wang, A. J. Lusis, P. Tontonoz, I. G. Schulman, Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc. Natl. Acad. Sci. U.S.A. , 22 August 2002 [e-pub ahead of print]. [Abstract] [Full Text]