Early fibroblast progenitor cell migration to the AngII-exposed myocardium is not CXCL12 or CCL2 dependent as previously thought.
Am J Pathol
; 183(2): 459-69, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23731726
ABSTRACT
Fibroblast progenitor cells (fibrocytes) are important to the development of myocardial fibrosis and are suggested to migrate to the heart via CXCL12 and chemokine ligand (CCL) 2. We hypothesized that if these chemokines are recruiting fibrocytes, disrupting their signaling will reduce early (3-day) fibrocyte infiltration and, consequently, fibrosis in the myocardium. C57/Bl6 and CCR2(-/-) mice were infused with saline or angiotensin (Ang) II, with or without CXC receptor 4 blockade (AMD3100). Hearts were assessed for chemokine up-regulation, immunofluorescence, and histological features. AngII caused early myocardial up-regulation of CXCL12 and CCL2, which corresponded to significant myocardial infiltration and fibrosis compared with controls. Animals receiving AMD3100 and/or with the genotype CCR2(-/-) failed to demonstrate reductions in infiltrate or fibrosis after 3 days of AngII, and AngII + AMD3100 animals showed exacerbated fibrocyte infiltration and fibrosis compared with AngII alone. CCR2(-/-) mice demonstrated significant reductions in myocardial fibrosis relative to wild type, but this was after 28 days of AngII infusion and was the result of reduced infiltrating cell proliferation. An alternative CCR2 ligand, CCL12, was found to be increasing infiltrating cell proliferation in the heart after AngII infusion, which we confirmed in vitro. In conclusion, early fibrocyte recruitment cannot be inhibited through modulating CXCL12 or CCL2, as previously thought. Ablating CCR2 signaling did confer myocardial fibrosis reductions, but these benefits were not observed until much later and were likely the result of modulated proliferation through ablating the CCL12-CCR2 interaction.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vasoconstritores
/
Angiotensina II
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Quimiocina CCL2
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Quimiocina CXCL12
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Fibroblastos
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Miocárdio
Limite:
Animals
Idioma:
En
Revista:
Am J Pathol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Canadá