Researchers at Columbia University have discovered how benign deposits of fat and cholesterol inside arteries may turn into exploding lesions that can block blood flow, causing heart attacks and strokes.
Currently, no treatments are available to prevent unstable lesions from breaking apart. Instead, treatments attempt to reduce lesion size and inflammation, but patients are vulnerable to heart attack or stroke until the lesions melt away.
The new findings suggest an alternative approach to treating atherosclerosis by targeting a specific molecular pathway inside the lesions. "The idea that you can go into a pre-existing lesion and attack a specific pathway that leads to rupture could become a powerful method to prevent the hundreds of thousands of deaths each year caused by atherosclerosis," says Dr. Ira Tabas, professor of medicine and anatomy & cell biology, and the senior author of two recent papers on this work, one published in the September issue of Nature Cell Biology and the other in the Sept. 2 issue of Proceedings of the National Academy of Sciences.
Atherosclerosis develops when excess cholesterol accumulates in spots inside arteries. The deposits attract macrophages, cells that ingest the cholesterol globules on the artery wall. The plaque grows as more fat is deposited and more macrophages move in.
Most people have the misperception that the plaque gets gradually bigger and closes off blood flow, says Dr. Tabas, but that's probably not a common pathological event since the vessel can compensate by getting bigger and by inducing the formation of new vessels.
"We all have plaques all over our arterial tree, but the vast majority do nothing," Dr. Tabas says. "Every once in a while, though, a plaque will rupture and expose certain molecules to the blood. Within minutes a clot will form and shut off blood flow to the heart or the brain. That's what kills us after years and years of plaque build-up."
Atherosclerosis researchers believe one factor contributing to rupture is the death of macrophages inside the lesion. The dead cells are thought to release substances that break up the plaque and promote the formation of the clots that block blood flow.
Lesion macrophages die from the cholesterol they ingest, but the method has been unclear. The new research shows that macrophages die as the cholesterol they ingest moves into the endoplasmic reticulum's (ER) membrane, which normally contains little cholesterol. When Drs. Tabas and research scientist Bo Feng, the lead author, blocked delivery of cholesterol to the organelle with a drug, mouse macrophages cultured in vitro survived despite engulfing large amounts of the fat. Details of these studies appear in Nature Cell Biology.
The researchers then tested their in vitro findings in living animals using a mouse strain unable to send cholesterol to the ER. Stopping the delivery to the ER not only prevented macrophage death in mice, but also prevented the mice from developing dangerous, unstable ("pre-rupture") lesions. Details of these experiments appear in PNAS. Future studies will be directed at looking at plaque rupture.
The studies raise the possibility that compounds like the one used in the cell culture experiments could be developed into drugs that prevent macrophage death in lesions. Stress signals from the ER of the dying cells could potentially be used to aim drugs directly at lesion macrophages while leaving others alone.
Columbia has filed a patent based on these ideas and Dr. Tabas is talking with pharmaceutical companies about drug development. Statins, the primary therapy for atherosclerosis today, are helpful but still cannot prevent 50 percent to 70 percent of heart attacks and strokes caused by ruptured lesions.
Many factors leading to lesion instability besides macrophage death will probably emerge in the future and offer additional drug targets. "Ten to 20 years from now, we'll realize there are several things that precipitate rupture," Dr. Tabas say, "but we have to be reductionist at first and focus on each individually."