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Diabetologia
Published in: Diabetologia 3/2014

01-03-2014 | Article

Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune–inflammatory responses in diabetic Apoe −/− mice

Authors: E. Di Marco, S. P. Gray, P. Chew, C. Koulis, A. Ziegler, C. Szyndralewiez, R. M. Touyz, H. H. H. W. Schmidt, M. E. Cooper, R. Slattery, K. A. Jandeleit-Dahm

Published in: Diabetologia | Issue 3/2014

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Abstract

Aims/hypothesis

Enhanced vascular inflammation, immune cell infiltration and elevated production of reactive oxygen species (ROS) contribute significantly to pro-atherogenic responses in diabetes. We assessed the immunomodulatory role of NADPH oxidase (NOX)-derived ROS in diabetes-accelerated atherosclerosis.

Methods

Diabetes was induced in male Apoe −/− mice with five daily doses of streptozotocin (55 mg kg−1 day−1). Atherosclerotic plaque size, markers of ROS and immune cell accumulation were assessed in addition to flow cytometric analyses of cells isolated from the adjacent mediastinal lymph nodes (meLNs). The role of NOX-derived ROS was investigated using the NOX inhibitor, GKT137831 (60 mg/kg per day; gavage) administered to diabetic and non-diabetic Apoe −/− mice for 10 weeks.

Results

Diabetes increased atherosclerotic plaque development in the aortic sinus and this correlated with increased lesional accumulation of T cells and CD11c+ cells and altered T cell activation in the adjacent meLNs. Diabetic Apoe −/− mice demonstrated an elevation in vascular ROS production and expression of the proinflammatory markers monocyte chemoattractant protein 1, vascular adhesion molecule 1 and IFNγ. Blockade of NOX-derived ROS using GKT137831 prevented the diabetes-mediated increase in atherosclerotic plaque area and associated vascular T cell infiltration and also significantly reduced vascular ROS as well as markers of inflammation and plaque necrotic core area.

Conclusions/interpretation

Diabetes promotes pro-inflammatory immune responses in the aortic sinus and its associated lymphoid tissue. These changes are associated with increased ROS production by NOX. Blockade of NOX-derived ROS using the NOX inhibitor GKT137831 is associated with attenuation of these changes in the immune response and reduces the diabetes-accelerated development of atherosclerotic plaques in Apoe −/− mice.
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Metadata
Title
Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune–inflammatory responses in diabetic Apoe −/− mice
Authors
E. Di Marco
S. P. Gray
P. Chew
C. Koulis
A. Ziegler
C. Szyndralewiez
R. M. Touyz
H. H. H. W. Schmidt
M. E. Cooper
R. Slattery
K. A. Jandeleit-Dahm
Publication date
01-03-2014
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 3/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-3118-3

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