Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis.
Atherosclerosis
; 238(2): 321-8, 2015 Feb.
Article
em En
| MEDLINE
| ID: mdl-25545330
ABSTRACT
OBJECTIVE:
Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis.METHODS:
High-fat diet-induced atherosclerosis was established in ApoE(-/-) mice crossed with gp130(F/F) knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130(F/F)Stat3(-/+)ApoE(-/-) mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE(-/-) and gp130(F/F)ApoE(-/-) mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68(+) macrophages, and plasma lipid and SAA profiles, were assessed.RESULTS:
Aortic plaque development and plasma triglyceride levels in gp130(F/F)ApoE(-/-) mice were significantly reduced (3-fold, P < 0.001) compared to ApoE(-/-) littermates. By contrast, in gp130(F/F)ApoE(-/-) mice, atherosclerotic plaques contained augmented CD68(+) macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE(-/-) mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130(F/F)ApoE(-/-) and gp130(F/F)Stat3(-/+)ApoE(-/-) mice were comparable, despite a significant (P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130(F/F)Stat3(-/+)ApoE(-/-) mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE(-/-) mice reconstituted with gp130(F/F)ApoE(-/-) (ApoE(F/FApoE)) or ApoE(-/-) (ApoE(ApoE)) bone marrow cells.CONCLUSIONS:
Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Aorta
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Doenças da Aorta
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Apolipoproteínas E
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Transdução de Sinais
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Aterosclerose
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Receptor gp130 de Citocina
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article