Liver CRP Production Linked To Atherosclerosis

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

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

As expected, hypercholesterolemic rabbits developedatherosclerotic plaques. Upon further examination, serum CRP levelswere found to positively correlate with plaque size. CRP was found inplaques of various stages, including early and advanced lesions, but itdid 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 mRNAlevels were measured by Northern blot and real-time RT-PCR. CRP mRNAwas only detected in liver obtained from atherosclerotic rabbits butwas undetectable in vascular cells or macrophages. Again, results wereconfirmed in human specimens: insignificant mRNA levels found inatherosclerotic aorta compared to high levels in liver. Finally, invitro analysis revealed that hepatocytes, but not macrophages,expressed CRP mRNA following stimulation by inflammatory molecules.

These data highlight a powerful role for the liver ingenerating 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 crimeis not necessarily evidence of guilt. Thus, CRP could be an innocentbystander, a victim, or possibly an atheroprotective force. Sun andcolleagues acknowledge that "further studies will be required toclarify whether decreasing CRP alone without changing the plasmacholesterol level can be beneficial for the treatment ofatherosclerosis."

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

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

This work involved collaborators at University of Tsukuba,Japan; University of Miyazaki, Japan; Kobe University School ofMedicine, Japan; Fukuoka University School of Medicine, Japan; SagaUniversity, 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 andpathophysiological significance. Am J Pathol 2005, 167: 1139-1148* These authors contributed equally to this work.