Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis.

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/F:ApoE)) 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.

• Authors: Gareth W Jones, Louise McLeod, Catherine L Kennedy, Steven Bozinovski, Meri Najdovska, Brendan J Jenkins
• Journal: Atherosclerosis (Atherosclerosis) Vol. 238 Issue 2 Pg. 321-8 (Feb 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 25545330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apolipoproteins E
• Il6st protein, mouse
• STAT3 Transcription Factor
• Serum Amyloid A Protein
• Stat3 protein, mouse
• Triglycerides
• Cytokine Receptor gp130

Topics

• Animals
• Aorta (metabolism, pathology)
• Aortic Diseases (blood, genetics, pathology, prevention & control)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (blood, genetics, pathology, prevention & control)
• Chemotaxis
• Cytokine Receptor gp130 (genetics, metabolism)
• Diet, High-Fat
• Disease Models, Animal
• Female
• Macrophages (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation
• Plaque, Atherosclerotic
• STAT3 Transcription Factor (genetics, metabolism)
• Serum Amyloid A Protein (metabolism)
• Signal Transduction
• Triglycerides (blood)