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

Research output: Contribution to journalArticleResearchpeer-review

152 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)128-137
Number of pages10
JournalCirculation Research
Volume105
Issue number2
DOIs
Publication statusPublished - 17 Jul 2009
Externally publishedYes

Keywords

  • Atherosclerosis
  • C-reactive protein
  • Platelets

Cite this

Eisenhardt, Steffen U. ; Habersberger, Jonathon ; Murphy, Andrew ; Chen, Yung-Chih ; Woollard, Kevin J. ; Bassler, Nicole ; Qian, Hongwei ; von zur Muhlen, Constantin ; Hagemeyer, Christoph E. ; Ahrens, Ingo ; Chin-Dusting, Jaye ; Bobik, Alex ; Peter, Karlheinz. / Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. In: Circulation Research. 2009 ; Vol. 105, No. 2. pp. 128-137.
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title = "Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques",
abstract = "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.",
keywords = "Atherosclerosis, C-reactive protein, Platelets",
author = "Eisenhardt, {Steffen U.} and Jonathon Habersberger and Andrew Murphy and Yung-Chih Chen and Woollard, {Kevin J.} and Nicole Bassler and Hongwei Qian and {von zur Muhlen}, Constantin and Hagemeyer, {Christoph E.} and Ingo Ahrens and Jaye Chin-Dusting and Alex Bobik and Karlheinz Peter",
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Eisenhardt, SU, Habersberger, J, Murphy, A, Chen, Y-C, Woollard, KJ, Bassler, N, Qian, H, von zur Muhlen, C, Hagemeyer, CE, Ahrens, I, Chin-Dusting, J, Bobik, A & Peter, K 2009, 'Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques', Circulation Research, vol. 105, no. 2, pp. 128-137. https://doi.org/10.1161/CIRCRESAHA.108.190611

Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. / Eisenhardt, Steffen U.; Habersberger, Jonathon; Murphy, Andrew; Chen, Yung-Chih; Woollard, Kevin J.; Bassler, Nicole; Qian, Hongwei; von zur Muhlen, Constantin; Hagemeyer, Christoph E.; Ahrens, Ingo; Chin-Dusting, Jaye; Bobik, Alex; Peter, Karlheinz.

In: Circulation Research, Vol. 105, No. 2, 17.07.2009, p. 128-137.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques

AU - Eisenhardt, Steffen U.

AU - Habersberger, Jonathon

AU - Murphy, Andrew

AU - Chen, Yung-Chih

AU - Woollard, Kevin J.

AU - Bassler, Nicole

AU - Qian, Hongwei

AU - von zur Muhlen, Constantin

AU - Hagemeyer, Christoph E.

AU - Ahrens, Ingo

AU - Chin-Dusting, Jaye

AU - Bobik, Alex

AU - Peter, Karlheinz

PY - 2009/7/17

Y1 - 2009/7/17

N2 - 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.

AB - 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.

KW - Atherosclerosis

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