Closing in on Plaques
"Almost everybody in the industrialized world has a legion of atherosclerotic plaques in their arteries,” says Dr. Ira Tabas, Vice-President of Research at Columbia University’s Department of Medicine. This isn’t as bad as it sounds. In fact, for mystery lovers, it’s the start of a puzzle as exciting as Sherlock Holmes’ deductions from the fact that a dog did not bark. If everybody has these plaques in such quantities, why don’t we all suffer heart disease as a result? “Only a few of the plaques are dangerous,” Dr. Tabas explains. “Most are asymptomatic. It’s those that progress to become what we call vulnerable plaques that cause problems.” While the majority of plaques remain safely attached to the arterial walls, vulnerable plaques may rupture or erode, letting materials loose in the bloodstream that can clog up vessels. Heart attack, stroke, and angina can be the result. From this perspective, the challenge is not so much to try to prevent atherosclerotic plaques, but rather to stop them from progressing to the dangerous vulnerable stage. This is Dr. Tabas’s goal, and recent discoveries in his lab make it seem closer than ever before. Dr. Tabas’s research focuses on two of the most important factors in the formation of vulnerable plaques: necrosis, or cell death, and inflammation. “The cells that die are white blood cells that normally fight infections, but here they’re getting involved in the plaques,” he says.

A Different Kind of ER
Further investigation implicated signaling pathways within the endoplasmic reticulum, or ER, of the white blood cells. However, knowing this wasn’t enough to start the search for a treatment. “One wouldn’t want to block ER signaling altogether, because it usually has beneficial effects,” Dr. Tabas says. “Normally, these pathways help build new proteins, or help repair cells in which there is a problem with protein construction.”
The key insight was that unusual amounts of cholesterol were present in the white blood cells that were involved in vulnerable plaque formation. Following up on this clue led to a vital discovery.

“When cholesterol builds up, it triggers a cascade of events,” Dr. Tabas says. “Excess cholesterol enters the ER and activates a signaling pathway that leads to the death of the white blood cell. And, before they die, they’re stimulated by cholesterol to produce inflammatory molecules.” In other words, too much cholesterol in the ER turns out to be critical in both of the factors of vulnerable plaque formation that Dr. Tabas set out to understand.

Blocking Inflammation
In the laboratory, Dr. Tabas has been able to show that blocking cholesterol from entering the ER blocks the death of the white blood cells. Work is currently underway to demonstrate that it can stop the inflammatory response that is also implicated in vulnerable plaques.
“The trick of finding a therapy is to be as specific as possible,” Dr. Tabas says. A problem that’s in the arteries of everyone in the industrialized world is too big to tackle. And a treatment that interferes with the healthy functioning of the body’s self-repair systems is doomed to fail. Finding the one key element that causes normal white blood cells to become part of dangerous plaques represents a feat of investigation worthy of Sherlock Holmes.

"the trick of finding a therapy is to be as specific as possible"

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