Craig LeMoult
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Columbia Researchers Identify Molecular
Process That Could Lead to Arterial Plaque Rupture

Following Failure of HDL Cholesterol Drug, Understanding Pathway to
Plaque Rupture Could Lead to Alternative Therapies

 

NEW YORK, December 12, 2006 -- Researchers from Columbia University Medical Center have uncovered a key molecular process that could cause plaque rupture in patients with atherosclerosis. The research, published today in the Proceedings of the National Academy of Science (PNAS) could lead to therapies to prevent plaque rupture, which can lead to heart attacks and strokes.

Heart researchers had believed until recently that drugs that increase good cholesterol (HDL) combined with statins that lower bad cholesterol (LDL) might cure atherosclerosis. However, with the withdrawal of Pfizer’s HDL-boosting torcetrapib from clinical testing, researchers are realizing that they may not be able to rely solely on drugs that raise HDL levels to prevent plaque rupture, at least for now. This new CUMC research suggests that atherosclerosis may be able to be controlled through an alternate mechanism that doesn't involve interfering with HDL.

“The recent failure of an HDL boosting therapy means it’s particularly important for us to consider alternative strategies and to understand the process behind the rupture of plaques,” said Ira Tabas, M.D., Ph.D., Richard J. Stock Professor & Vice-Chairman of Research, and professor of Medicine and Anatomy & Cell Biology at Columbia University Medical Center. “Our hope is that this research will lead to alternative therapies to prevent plaque rupture and resulting strokes and heart attacks.”

The PNAS paper explains what causes the death of macrophages, white blood cells that accumulate in the cholesterol-laden plaques on the inside of arteries in patients with atherosclerosis. Those dead macrophages, which pile up to form what Dr. Tabas calls a “macrophage graveyard” or necrotic core, are an important cause of plaque rupture. The rupture can stimulate the formation of clots that can block blood flow and cause heart attacks and strokes. The biggest danger in atherosclerosis comes not from the plaque growing to a point that it blocks the artery, as is often believed, but from smaller plaques becoming unstable and prone to rupture.

The Columbia researchers discovered that macrophages in the plaques die when two receptors on the cell's surface - TLR4 and SRA - are activated at the same time. When activated alone, TLR4 keeps the macrophage alive. However, the Columbia researchers found that when SRA was also activated, SRA shut down TLR4 and killed the cell.

The findings also may be important in the fight against a completely different disease: tuberculosis. Macrophages usually fight infection, but virulent TB strains escape the immune system by infecting, and essentially neutralizing, macrophages in the lung. Developing a therapy that uses TLR4 and SRA to kill these TB-laden macrophages could be a revolutionary new treatment for one of the biggest killers in developing countries.

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Columbia University Medical Center provides international leadership in pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians & Surgeons, the College of Dental Medicine, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions.