New research shows that levels of C-reactive protein (CRP), produced by the liver and not at the lesion site, correlate with the degree of atherosclerosis. The paper by Sun et al., "C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance," appears in the October issue of The American Journal of Pathology and is accompanied by a commentary.

C-reactive protein (CRP) is a hallmark of inflammation and tissue damage, as in arthritis or infection. It is also widely touted as a marker for cardiovascular disease, with doctors using patient CRP levels to improve risk assessment. However, whether CRP is merely a risk marker or is actually a contributing factor of cardiovascular disease has remained controversial.

To address these issues, Dr. Jianglin Fan's group examined the role of CRP in two rabbit models of atherosclerosis: high cholesterol diet or LDL receptor deficiency. Rabbits represent highly suitable models as they quickly form atherosclerotic plaques in response to high serum cholesterol, and rabbit CRP shares 70% homology with human CRP.

As expected, hypercholesterolemic rabbits developed atherosclerotic plaques. Upon further examination, serum CRP levels were found to positively correlate with plaque size. CRP was found in plaques of various stages, including early and advanced lesions, but it did not appear to associate with macrophages, as had been suggested. Similar results were seen in human aortic lesions.

To determine where CRP protein was being produced, CRP mRNA levels were measured by Northern blot and real-time RT-PCR. CRP mRNA was only detected in liver obtained from atherosclerotic rabbits but was undetectable in vascular cells or macrophages. Again, results were confirmed in human specimens: insignificant mRNA levels found in atherosclerotic aorta compared to high levels in liver. Finally, in vitro analysis revealed that hepatocytes, but not macrophages, expressed CRP mRNA following stimulation by inflammatory molecules.

These data highlight a powerful role for the liver in generating the CRP that is associated with atherosclerotic lesions. Nonetheless, we are still left wondering whether CRP is a cause, result, or both of heart disease, as presence at the scene of a crime is not necessarily evidence of guilt. Thus, CRP could be an innocent bystander, a victim, or possibly an atheroprotective force. Sun and colleagues acknowledge that "further studies will be required to clarify whether decreasing CRP alone without changing the plasma cholesterol level can be beneficial for the treatment of atherosclerosis."

This study uncovers new approaches for the treatment of atherosclerosis. In the future, Dr. Fan hopes to "test whether any therapeutic inhibition of CRP levels can be beneficial for [coronary heart disease] patients or preventive from coronary artery syndrome or plaque rupture. Importantly, we will target the liver rather than the vascular wall (such as macrophages) for the inhibition of CRP."

Research was supported by grants-in-aid for scientific research by MEXT (KAKENHI.16390089 and 16659099), the Takeda Science Foundation, Ono Medical Research Foundation and Novartis Foundation for the Promotion of Science, and a grant from the Center for Tsukuba Advanced Research Alliance (TARA) at the University of Tsukuba.

This work involved collaborators at University of Tsukuba, Japan; University of Miyazaki, Japan; Kobe University School of Medicine, Japan; Fukuoka University School of Medicine, Japan; Saga University, Japan; and Morehouse School of Medicine, Atlanta, Georgia, USA.

Sun H*, Koike T*, Ichikawa T, Hatakeyama K, Shiomi M, Zhang B, Kitajima S, Morimoto M, Watanabe T, Asada Y, Chen Y E, Fan J: C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance. Am J Pathol 2005, 167: 1139-1148
* These authors contributed equally to this work.

Commentary: Torzewski J: C-reactive protein and atherogenesis - new insights from an established animal model: Am J Pathol 2005, 167:923-925

The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.

Audra Cox
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