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Release: June 28, 2002

NOTE TO EDITORS: The following news release describes a study led by investigators at the University of California Davis School of Medicine and Medical Center. William Nauseef, M.D., University of Iowa professor of internal medicine, was part of the research team. He is available for comment most of the day Friday, June 28 at (319) 356-1739. For a copy of the UC Davis release, contact or visit

UI researcher contributes to study linking a specific protein to atherosclerosis

A protein that normally plays a pivotal role in combating bacterial infections can also contribute to inflammatory disease in blood vessels by altering the availability of nitric oxide, according to a study published by University of California at Davis investigators and others, including a University of Iowa physician-scientist.

The findings on the protein myeloperoxidase (MPO) appear in the June 28 issue of Science. The paper's lead author was Jason Eiserich, Ph.D., assistant professor of internal medicine and human physiology at the UC Davis School of Medicine and Medical Center. The results have implications for understanding and treating atherosclerosis -- the build-up of fats, cholesterol, cellular debris, calcium and other substances that damage the inner lining of arteries and result in significant disease and death. The research team included William Nauseef, M.D., UI professor of internal medicine and a faculty member of the UI Inflammation Program.

Nauseef heads a long-standing project that studies the structure and function of MPO, including the functional consequences of different genetic causes of inherited human MPO deficiency. In previous work his lab identified several specific mutations in the MPO gene that result in the absence of normally functioning MPO in humans.

"We developed a system to characterize the functional effects of different genotypes of MPO deficiency," said Nauseef, who also is a staff physician and researcher with the Veterans Affairs Medical Center in Iowa City. "We created cell lines that express normal MPO and lines that mimic the patients' defects by expressing the mutant, nonfunctional form of MPO. Jason Eiserich and his team used both of these cells as a source for their tests, and they were able to demonstrate that the observed changes in blood vessel reactivity were due to the presence of active MPO."

MPO is normally found in the circulating white blood cells that respond to acute infection by forming pus. MPO catalyzes the generation of hypochlorous acid, or bleach, and is essential in efficiently wiping out bacteria. However, the protein also can participate in inflammatory events that are independent of infection, such as the acute inflammatory responses seen in gout, rheumatoid arthritis, many allergic reactions, and stress-related inflammation.

"From the point of view of the host, it's good when MPO kills bacteria and contributes to resolving an infection, but it's bad when, for example, it's participating in an acute arthritic attack in a joint such as the knee," Nauseef said.

Blood vessels react to different chemical influences, including nitric oxide, which is also known as the "vascular relaxing factor." As such, this molecule helps regulate blood pressure, inhibits blood clotting and prevents narrowing of the arteries.

Normally, MPO combines with hydrogen peroxide in the presence of chloride to kill bacteria. However, the investigators found that MPO combines with hydrogen peroxide and other molecules to form free radicals that then react with nitric oxide. This chemical reaction thereby reduces the amount of nitric oxide available to mediate vessel relaxation, thus changing the body's ability to regulate blood vessel reactivity.

Nauseef said he hopes to continue studying the structural and genetic factors underlying normal MPO activity.

"Since none of the cells normally present in a fatty plaque normally possess MPO, the identification of MPO in blood vessels has never been fully explained," he said. "We believe that certain cells within plaque acquire the capacity to express the MPO gene because of special proteins such as cytokines produced within the plaque environment."

If that is true, Nauseef added, then determining the factors that regulate MPO gene expression might make it possible to interrupt the cycle, as a therapeutic intervention.

"There's long been a suspicion that MPO has a role in atherosclerosis," Nauseef said. "This finding advances that notion one step further. The study emphasizes that atherosclerosis is a complex, multifactorial inflammatory disease and reflects biology far more involved than simply excess fat consumption."

The Department of Veterans Affairs funded Nauseef's research on MPO and MPO deficiency for this study, and the work was accomplished at the Iowa City VA Medical Center. The VA has funded Nauseef's MPO research since 1984.

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