C-REACTIVE PROTEIN MODULATION OF INFLAMMATION IN ACUTE CORONARY ARTERY DISEASE
Janos G. Filep, M.D., University of Montreal, Montreal, QC, Canada
C-reactive protein (CRP) is an acute-phase reactant and an active regulator of innate immunity. Clinical studies have shown that elevated baseline serum CRP levels confer, albeit to varying degrees, additional prognostic value for future coronary artery disease (CAD) and death and may be useful for risk-guided therapy. CRP has been implicated in multiple aspects of atherogenesis and acute CAD; however, whether CRP plays a direct causal role in these events remains controversial. Studies in rodents yielded conflicting results on atherosclerosis development. CRP has at least two conformationally distinct forms, native pentameric (p) CRP and monomeric (m)CRP. Loss of pentameric symmetry in pCRP, yielding mCRP, is associated with expression of distinct bioactivities. Using CRP isomer-selective antibodies, we detected mCRP, but not native CRP in human coronary artery atherosclerotic lesions with more pronounced mCRP staining in advanced fibro-fatty plaques than fatty streak lesions. The mCRP staining frequently co-localized with neutrophils and macrophages in advanced lesions. In vitro, mCRP is considerably more potent activator of human coronary artery endothelial cells and monocytes than pCRP, whereas mCRP and pCRP exert opposing actions on neutrophil trafficking and apoptosis through distinct Fc-gamma receptors and lipid rafts. Unlike pCRP, mCRP is susceptible for proteolysis, resulting in peptide 201-206 that exhibits potent anti-inflammatory and anti-platelet activities. These findings may explain how sequential conformational changes in CRP’s structure could lead to expression of distinct biological activities that may modulate inflammation underlying plaque destabilization and acute CAD.
(Grant support: CIHR).