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(Circulation Research. 2009;105:128.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Dissociation of Pentameric to Monomeric C-Reactive Protein on Activated Platelets Localizes Inflammation to Atherosclerotic Plaques

Steffen U. Eisenhardt, Jonathon Habersberger, Andrew Murphy, Yung-Chih Chen, Kevin J. Woollard, Nicole Bassler, Hongwei Qian, Constantin von zur Muhlen, Christoph E. Hagemeyer, Ingo Ahrens, Jaye Chin-Dusting, Alex Bobik, Karlheinz Peter

From the Baker Heart and Diabetes Institute (S.U.E., J.H., A.M., Y.-C.C., K.J.W., N.B., H.Q., C.E.H., I.A., J.C.-D., A.B., K.P.), Melbourne, Australia; and Department of Plastic and Hand Surgery (S.U.E.) and Department of Cardiology (C.v.z.M.), University of Freiburg Medical Center, Germany.

Correspondence to Steffen U. Eisenhardt, MD, University of Freiburg Medical Center, Department of Plastic and Hand Surgery, Hugstetter Strasse 55, 79106 Freiburg, Germany. E-mail steffen.eisenhardt{at}uniklinik-freiburg.de

C-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentamer (pentameric CRP) in plasma. The in vivo existence of monomeric (m)CRP has been postulated, but its function and source are not clear. We show that mCRP is deposited in human aortic and carotid atherosclerotic plaques but not in healthy vessels. pCRP is found neither in healthy nor in diseased vessels. As source of mCRP, we identify a mechanism of dissociation of pCRP to mCRP. We report that activated platelets, which play a central role in cardiovascular events, mediate this dissociation via lysophosphatidylcholine, which is present on activated but not resting platelets. Furthermore, the dissociation of pCRP to mCRP can also be mediated by apoptotic monocytic THP-1 and Jurkat T cells. The functional consequence is the unmasking of proinflammatory effects of CRP as demonstrated in experimental settings that are pathophysiologically relevant for atherogenesis: compared to pCRP, mCRP induces enhanced monocyte chemotaxis; monocyte activation, as determined by conformational change of integrin Mac-1; generation of reactive oxygen species; and monocyte adhesion under static and physiological flow conditions. In conclusion, we demonstrate mCRP generation via pCRP dissociation on activated platelets and H₂O₂-treated apoptotic THP-1 and Jurkat T cells, thereby identifying a mechanism of localized unmasking of the proinflammatory properties of CRP. This novel mechanism provides a potential link between the established cardiovascular risk marker, circulating pCRP, and localized platelet-mediated inflammatory and proatherogenic effects.

Key Words: C-reactive protein • atherosclerosis • platelets

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