Conformationally Altered C-Reactive Protein Capable of Binding to Atherogenic Lipoproteins Reduces Atherosclerosis.
C-reactive protein
atherosclerosis
inflammation
low-density lipoprotein
phosphocholine
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
21
05
2020
accepted:
03
07
2020
entrez:
28
8
2020
pubmed:
28
8
2020
medline:
13
4
2021
Statut:
epublish
Résumé
The aim of this study was to test the hypothesis that C-reactive protein (CRP) protects against the development of atherosclerosis and that a conformational alteration of wild-type CRP is necessary for CRP to do so. Atherosclerosis is an inflammatory cardiovascular disease and CRP is a plasma protein produced by the liver in inflammatory states. The co-localization of CRP and low-density lipoproteins (LDL) at atherosclerotic lesions suggests a possible role of CRP in atherosclerosis. CRP binds to phosphocholine-containing molecules but does not interact with LDL unless the phosphocholine groups in LDL are exposed. However, CRP can bind to LDL, without the exposure of phosphocholine groups, if the native conformation of CRP is altered. Previously, we reported a CRP mutant, F66A/T76Y/E81A, generated by site-directed mutagenesis, that did not bind to phosphocholine. Unexpectedly, this mutant CRP, without any more conformational alteration, was found to bind to atherogenic LDL. We hypothesized that this CRP mutant, unlike wild-type CRP, could be anti-atherosclerotic and, accordingly, the effects of mutant CRP on atherosclerosis in atherosclerosis-prone LDL receptor-deficient mice were evaluated. Administration of mutant CRP into mice every other day for a few weeks slowed the progression of atherosclerosis. The size of atherosclerotic lesions in the aorta of mice treated with mutant CRP for 9 weeks was ~40% smaller than the lesions in the aorta of untreated mice. Thus, mutant CRP conferred protection against atherosclerosis, providing a proof of concept that a local inflammation-induced structural change in wild-type CRP is a prerequisite for CRP to control the development of atherosclerosis.
Identifiants
pubmed: 32849641
doi: 10.3389/fimmu.2020.01780
pmc: PMC7431523
doi:
Substances chimiques
Cholesterol, LDL
0
C-Reactive Protein
9007-41-4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1780Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR068787
Pays : United States
Informations de copyright
Copyright © 2020 Pathak, Singh, Thewke and Agrawal.
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