title: A redox switch in C-reactive protein modulates activation of endothelial cells.
abstract: C-reactive protein (CRP) has been implicated in the regulation of inflammation underlying coronary artery disease; however, little is known about the molecular mechanisms responsible for the expression of its pro- or anti-inflammatory activities. Here, we have identified the intrasubunit disulfide bond as a conserved switch that controls the structure and functions of CRP. Conformational rearrangement in human pentameric CRP to monomeric CRP (mCRP) is the prerequisite for this switch to be activated by reducing agents, including thioredoxin. Immunohistochemical analysis revealed 36-79% colocalization of thioredoxin and mCRP in human advanced coronary atherosclerotic lesions. Nonreduced mCRP was largely inert in activating human coronary artery endothelial cells (HCAECs), whereas reduced or cysteine-mutated mCRP evoked marked release of IL-8 and monocyte chemoattractant protein-1 from HCAECs, with ~50% increase at a concentration of 1 μg/ml. Reduced mCRP was ~4 to 40-fold more potent than mCRP in up-regulating adhesion molecule expression, promoting U937 monocyte adhesion to HCAECs, and inducing cytokine release from rabbit arteries ex vivo and in mice. These actions were primarily due to unlocking the lipid raft interaction motif. Therefore, expression of proinflammatory properties of CRP on endothelial cells requires sequential conformational changes, i.e., loss of pentameric symmetry followed by reduction of the intrasubunit disulfide bond.
authors.affiliation: Ministry of Education Key Laboratory of Arid and Grassland Ecology, Institute of Biophysic, China.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Wang
authors.forename: Shang-Rong
authors.initials: SR
authors.lastname: Ji
authors.forename: Cai-Juan
authors.initials: CJ
authors.lastname: Bai
authors.forename: Driss
authors.initials: D
authors.lastname: El Kebir
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Li
authors.forename: Jing-Ming
authors.initials: JM
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Santiago
authors.initials: S
authors.lastname: Costantino
authors.forename: Hai-Hong
authors.initials: HH
authors.lastname: Zhou
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Potempa
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: János G
authors.initials: JG
authors.lastname: Filep
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002097:C-Reactive Protein / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000378:metabolism; D015922:Complement C1q / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D011817:Rabbits
chemical_list: D008078:Cholesterol, LDL; D015922:Complement C1q; D002097:C-Reactive Protein