EMBARGOED for 5 pm EDT Monday, Sept. 9, 2002 by Proceedings of the National Academy of Sciences

UCSD Team Identifies Potential Role of CRP
In Development of Atherosclerosis

Another piece of the complex puzzle of how inflammation is involved in heart attacks and strokes has been discovered by researchers at the University of California, San Diego (UCSD) School of Medicine.

Their findings demonstrate that C-reactive protein (CRP) binds to oxidized low density lipoprotein (LDL), implicating the interaction of CRP and oxidized LDL as a potential trigger for the cascade of events leading to atherosclerosis. This form of artery disease is characterized by the buildup of fatty deposits and chronic inflammation along the artery wall, eventually leading to heart attack.

Published in the online edition of Proceedings of the National Academy of Sciences (PNAS) the week of Sept. 16, 2002, the study by the UCSD researchers pinpoints how CRP attaches itself to oxidized LDL, the so-called "bad cholesterol" that accumulates in the artery wall and generates atherosclerotic plaques. LDL is the major cholesterol carrying particles. When they enter the artery wall from the circulation, they are believed to be modified by oxidation. It is this "oxidized LDL" that is thought to be the culprit leading to inflammation and cholesterol accumulation.

Mi-Kyung Chang, M.D., first author 

"Our study points out that CRP is not merely a marker of future cardiovascular events, as most people believe, but it actually binds to oxidized LDL and apoptotic or dying cells, giving it a potential role in development or modulation of atherosclerosis, as well as in other inflammatory disease," said Mi-Kyung Chang, M.D., an assistant project scientist and the first author of the paper in PNAS.

In the new studies, the UCSD team showed that CRP binds to oxidized LDL through the recognition of phosphocholine, a part of an oxidized molecule on the surface that is exposed when LDL undergoes oxidation.

Noting that there is an accumulation of dead and dying cells (apoptotic cells) in atherosclerotic lesions and that these cells are under increased oxidative stress, the UCSD researchers also determined that CRP binds to these cells in a similar manner as it recognizes oxidized LDL.

CRP is conventionally regarded as a first-line defense of the immune system against invading pathogens and confers protection to humans by removing pathogens. Recently, CRP has been reported as a useful marker for predicting future atherosclerotic cardiovascular events, but the basis for this correlation remains unclear.

Although scientists still do not understand all the steps in the development of atherosclerosis, it is known that oxidized LDL in the artery wall are taken up (engulfed) by macrophages, scavenger cells that have been drawn to the site by oxidized LDL. When they become engorged with the oxidized LDL, the macrophages become "foam cells," the hallmark of atherosclerotic plaques. It is possible that CRP may bind to oxidized LDL and further enhance the uptake into cells.

Joseph Witztum, M.D., and Mi-Kyung Chang, M.D.

The paper's senior author, Joseph Witztum, M.D., professor of medicine, added that cholesterol is still a key player in coronary heart disease. He said that CRP may be working in its "correct role" as part of the immune response to the toxic oxidized LDL and may help promote its clearance.

"If you have low levels of LDL, and thus, low levels of oxidized LDL, then CRP may be of benefit," Witztum said. "However, when there is an overwhelming accumulation of LDL, and thus oxidized LDL, in its attempt to help clear the toxic particle, the CRP may actually make things worse. It may cause more oxidized LDL to be taken up into macrophage scavenger cells, which in turn cause cholesterol accumulation a sort of 'Trojan horse'."

For the past 20 years, the Witztum lab at UCSD, in collaboration with UCSD professor of medicine Daniel Steinberg, M.D., Ph.D., has pioneered the role of oxidized LDL as a major contributing factor for the development of atherosclerosis. In particular, the Witztum lab has been studying immunological response to oxidized LDL and its impact on development and modulation of atherosclerosis. Recently, the Witztum team found that many mouse antibodies that are specific to oxidized LDL are identical to "T15" type natural antibodies that have been extensively studied for 30 years by immunologists for their recognition of S. pneumoniae, the most common cause of pneumonia. T15 also binds to phosphocholine present on pathogens and provides a protective immune defense against those pathogens.

As both T15 antibody and CRP recognize the same molecule, phosphocholine, Chang reasoned that CRP might bind to oxidized LDL, but not native LDL that does not expose phosphocholine. Indeed, Chang and colleagues showed that CRP does bind to oxidized LDL as well as apoptotic cells through the recognition of phosphocholine. Therefore, CRP is now a novel immune response to oxidized LDL, along with macrophages and T15 antibodies, through the recognition of the same phosphocholine molecule, which is also present on many infectious pathogens.

Studies are now underway to determine whether CRP is protective, or could actually cause harm.

The UCSD research was funded by the National Institutes of Health. In addition to Chang and Witztum, additional authors were Christoph J. Binder, Ph.D., post doctoral fellow, and Michael Torzewski, M.D., visiting scholar, UCSD Department of Medicine.

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