Columbia Researchers Discover Signal That Turns Minor Cholesterol Deposits Into Deadly Lesions
New York, NY – August 14, 2003 – In two new papers, medical scientists at Columbia University have discovered how benign deposits of fat and cholesterol inside arteries may turn into exploding lesions that block blood flow and cause heart attacks and strokes. The research suggests a new approach to treating atherosclerosis and preventing these events by altering a specific molecular pathway inside the lesions. Drugs that block the pathway could be given to people at high risk until diet and exercise slowly melt the lesions away, says the papers’ senior author, Dr. Ira Tabas, professor of medicine and cell biology at Columbia University College of Physicians and Surgeons.
Currently there are no treatments available to prevent unstable lesions from breaking apart. Instead, treatments attempt to reduce the size of lesions, but patients are vulnerable to heart attack or stroke until the lesions melt away. “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,” Dr. Tabas says.
The research is published in the September issue of Nature Cell Biology and the August 11 issue of Proceedings of the National Academy of Sciences. The groups of Dr. David Ron, professor of medicine and cell biology at New York University School of Medicine; Dr. Andrew Marks, chairman of the Department of Physiology and Cellular Biophysics and Director of the Center for Molecular Cardiology at Columbia University College of Physicians & Surgeons; and Dr. Edward Fisher, professor of medicine at Mount Sinai School of Medicine, collaborated with Dr. Tabas. The lead author on both papers was Dr. Bo Feng, an associate research scientist in Dr. Tabas' laboratory.
Atherosclerosis develops when excess cholesterol accumulates in spots on the inside of 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. Plaques cause heart attacks and strokes when they break apart. Within minutes, large clots form around the ruptured plaque and abruptly shut off blood flow to the heart or the brain.
Atherosclerosis researchers believe that plaques may rupture after cholesterol damages and then kills the macrophages. The dead cells are thought to release substances that break up the plaque and promote clot formation. But the method by which cholesterol kills macrophages has been unclear.
The new research shows that the macrophages die as the cholesterol they ingest moves to an organelle inside the cells and damages it beyond repair. The organelle, the endoplasmic reticulum (ER), is responsible for making the cell's proteins.
The scientists first showed cholesterol delivery to the ER is responsible for macrophage death in experiments where macrophages from mice were grown in tissue culture surrounded by cholesterol. Usually the cholesterol kills the cells, but when delivery of cholesterol to the organelle was stopped with a drug, the cells survived. Details of these studies appear in Nature Cell Biology.
The researchers took the findings one step further and tested the effect of stopping ER cholesterol delivery in living animals. This time they took advantage of a genetic mutation in mice that stops cholesterol delivery to the organelle. They found that stopping the delivery to the ER not only prevented macrophage death in mice, but also prevented the mice from developing dangerous, unstable lesions. Details of these experiments appear in PNAS.