Biochemical Signals Associated With Atherosclerosis May Damage Other Organs

The findings suggest that the effects of atherosclerosis are more widespread than previously believed, the researchers say. The study could lead to new targets for developing drugs that could help prevent or reduce these chemical changes that appear to accompany heart disease, the number one cause of death in the U.S. Their study was presented today at the 235th national meeting of the American Chemical Society.

"Our findings add new knowledge to the big melting pot of this complex disease called atherosclerosis," says study leader Rita Upmacis, Ph.D., a chemist at Weill Medical College of Cornell University in New York. "I anticipate that future research will establish whether the harmful protein modifications we observed in animal organs can be prevented and provide the basis of new treatments for the disease."

Scientists are closing in on the root causes of the disease. One of the more promising lines of research focuses on the interaction between certain highly reactive nitrogen molecules and proteins. Under certain conditions, this interaction produces nitrotyrosine, which has been linked to Alzheimer's, arthritis, cancer, and other disorders. However, scientists know little about the role of nitrotyrosine in atherosclerosis.

In the new study, Upmacis and colleagues worked with laboratory mice that have atherosclerosis. These mice are widely used in atherosclerosis research that cannot be done in humans. Mice that are genetically prone to atherosclerosis and fed a high-fat diet developed high levels of nitrotyrosine in their heart, lung, liver, and kidney. By contrast, mice that were fed regular diets showed no such increase. The rise in nitrotyrosine levels suggests that high-fat diets in animals with atherosclerosis can help trigger nitrotyrosine accumulation in the proteins of various organs, the scientists say.

Upmacis and colleagues also conducted a related experiment in atherosclerotic mice lacking the gene that makes nitric oxide synthase (iNOS), an enzyme that orchestrates accumulation of nitrotyrosine in proteins. In association with prior findings that iNOS gene deletion limits the formation of atherosclerotic plaques, the new study showed that nitrotyrosine accumulation in proteins is reduced in diverse organs when iNOS is absent.

"The findings support an emerging view that iNOS could be a new target for treating atherosclerosis and that limiting nitrotyrosine accumulation in the lungs, liver, and other organs could help fight the damaging effects of the disease," Upmacis says. "But the trick will be to develop a drug to block this pathway without causing any unwanted side effects."

Potentially, the accumulation of nitrotyrosine in the blood can be utilized as a diagnostic test to track atherosclerosis and provide a clearer picture of damage to organs, the researchers say.

Funding for the study was provided by the National Institutes of Health and Philip Morris (USA and International).