Keeping artery plaques under control

Calming a gene called CHOP may stabilize plaques and limit clot formation

Toning down a gene called CHOP might lessen the risk of arterial plaque ruptures that can cause heart attacks and strokes, according to a study in mice that appears in the May 6 Cell Metabolism.

Plaques that form inside arteries are the hallmark of atherosclerosis and contain a witches’ brew of cholesterol, inflammatory proteins, immune cells, calcium and other components. Plaques are ticking time bombs because they can rupture or even leak, causing blood to clot up and block the vessel. In a coronary artery, that’s a heart attack. In the brain, a stroke.

Yet very few of these bombs go off. By most estimates, only 2 to 3 percent of plaques ever leak and trigger clotting.

“The million-dollar question is, what is it about these 2 to 3 percent of lesions that makes them progress to cause disease?” says cell biologist and physician Ira Tabas of Columbia University.

Scientists know part of the answer. Composition of a plaque matters, Tabas says. A plaque that has dying cells in the middle — a necrotic core — is more prone to leakage, since such cells spill their contents faster than crews can clean up. But the chain of events leading to excessive cell death and leakage is less clear.

The CHOP gene has been suspected in plaque leakage, so Tabas and his colleagues investigated whether CHOP can regulate cell death and contribute to the formation of necrotic plaques in mice.

The researchers tested CHOP’s role in genetically engineered mice susceptible to forming plaques. Some mice lacked the CHOP gene while others still had it. After 10 weeks on a rich Western diet, all the mice had high fat levels in the blood and arterial plaques. But mice lacking CHOP made plaques that were one-third smaller than those in mice with normal CHOP. And mice without CHOP also had only half as much plaque necrosis as the others, the researchers find.

Tabas and his team looked specifically at macrophages, immune cells that commonly accumulate in plaques. Macrophages normally engulf and dispose of dying cells but can get damaged and need recycling themselves. Macrophages and other cells are “stressed” by imbalances in the plaque, such as the presence of excess fats or aberrant metabolic conditions, as in diabetes, Tabas says. The new research clarifies that the CHOP gene is instrumental in triggering aberrant cell death in plaques when confronted with such outside stress factors, he says.

Whether the upshot is too many cells dying or a bogged-down cleanup process or both, the result is a necrotic core and a high-risk plaque, he says.

The authors of this study “show a good, solid connection” between the stress factors, CHOP activation and cell death, says Joel Habener, a molecular biologist at Harvard Medical School and Massachusetts General Hospital in Boston. “With this increased cell death, you get detritus and the demolition of more cells, like a forest where the dead wood keeps piling up.” 

What’s more, this poor deposition of dead macrophages in the plaque attracts inflammatory proteins and cells, which further contribute to the stress on surviving macrophages, he says. “Inflammation can work for us or against us,” he says. “Uncontrolled inflammation is probably going on here.”

CHOP deactivation in people may prevent macrophages and other cells in the vicinity of a plaque from dying at a rate faster than the cells can be cleaned up, Tabas says.

Mice lacking CHOP remained healthy, but Tabas says therapy in people would likely tone down the protein encoded by CHOP, not completely eliminate the gene.

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