Researchers say they have evidence to explain what separates your average blood vessel plaque from those that are at high risk for triggering the development of dangerous--even fatal--blood clots. The findings in the May issue of Cell Metabolism, a Cell Press publication, suggest that drugs designed to tackle a form of cellular stress might be useful in treating heart disease, which is the number one killer and getting worse, according to the researchers.
"Just about everybody in our society has atherosclerosis by the time we reach 20," said Ira Tabas of Columbia University in New York. In atherosclerosis, lipid, inflammation and white blood cells known as macrophages build up at various spots along blood vessel walls, he explained. The vast majority of these lesions will never cause any problem whatsoever, but the rest--some 2 percent of all plaques--will eventually lead to the development of an acute blood clot and to heart attack, sudden death, or stroke.
"The billion dollar question is why 98 percent cause no problem, and 2 percent do."
Their report adds support to the notion that so-called endoplasmic reticulum (ER) stress together with the body's natural way of coping with that stress is one answer.
The ER is a cellular component that serves two major functions: it is the site where new proteins are made, folded, and transported, and it is also the central storage depot for the cell's calcium and controls its release, Tabas explained. When insults to the cell throw those functions off kilter, cells handle the imbalance via a pathway known as the unfolded protein response (UPR). If times get really tough, that pathway simply kills off the cells that are suffering. That decision to die is commandeered by an ER stress effector known as CHOP.
"When cells die, it's OK as long as it's not en masse," Tabas said, noting that we lose billions of cells every day. "It's a wonderful path to keep the ER in check, and by killing a cell here and there because of uncorrectable ER stress, the pathway protects the whole organism. In pathologies, however, this pathway gets overexuberant." Indeed, scientists are increasingly coming to the realization that ER stress and the body's "overexuberant" reaction to it are common features of aging, underlying neurodegenerative disease, and diabetes, for example.
In the case of atherosclerosis, ER stress within plaques could lead to the massive death of cells--and of macrophages in particular--leading to the generation of a structure called the "necrotic core." Those necrotic cores are known to be a defining feature of plaques that are vulnerable to rupture and blood clot formation. While earlier studies had suggested a correlation between ER stress and vulnerable plaques, the new study is the first to show a clear causal connection between the two, Tabas said.
His group studied two separate strains of mice, each carrying a specific genetic alteration that makes them especially prone to develop atherosclerosis. The mice also lacked CHOP, disabling the prodeath branch of the ER stress pathway.
When fed a diet high in fat and cholesterol for 10 weeks, one strain of those CHOP deficient mice with atherosclerosis developed smaller lesions than mice with CHOP, they report. Most importantly, cell death and plaque necrosis dropped by about 50 percent. The second strain of atherosclerotic mice showed essentially the same result.
Despite the fact that evidence had pointed to ER stress and the UPR before, Tabas said the result--and particularly the magnitude of the effect--still came as a considerable surprise.
"The fact that we were able to isolate one gene encoding one protein with such a profound effect on plaque necrosis was a big surprise," he said. That's because there could be many other processes at work, including some that might compensate for CHOP loss.
The findings in mice could have some real implications in the clinic, Tabas added.
"The results of this study, together with recent findings showing expression of CHOP in vulnerable human atherosclerotic plaques, suggest that the CHOP pathway may be a potential therapeutic target related to the formation of dangerous atheromata," the researchers concluded. "In particular, it will be interesting to determine whether so-called chemical chaperones, which have been successfully used in other animal models of UPR-associated diseases, have a beneficial effect on advanced atherosclerotic lesion progression."
The researchers include Edward Thorp, Columbia University, New York, NY; Gang Li, Columbia University, New York, NY; Tracie A. Seimon, Columbia University, New York, NY; George Kuriakose, Columbia University, New York, NY; David Ron, Skirball Institute, New York University Medical Center, New York, NY; and Ira Tabas, Columbia University, New York, NY.