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Diabetologia
Published in: Diabetologia 3/2010

01-03-2010 | Article

Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes

Authors: A. Koïtka, Z. Cao, P. Koh, A. M. D. Watson, K. C. Sourris, L. Loufrani, A. Soro-Paavonen, T. Walther, K. J. Woollard, K. A. M. Jandeleit-Dahm, M. E. Cooper, T. J. Allen

Published in: Diabetologia | Issue 3/2010

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Abstract

Aims/hypothesis

Most of the known actions of angiotensin II have been considered primarily to be the result of angiotensin II subtype 1 receptor activation. However, recent data suggest that the angiotensin II subtype 2 receptor (AT2R) may modulate key processes linked to atherosclerosis. The aim of this study was to investigate the role of AT2R in diabetes-associated atherosclerosis using pharmacological blockade and genetic deficiency.

Methods

Aortic plaque deposition was assessed in streptozotocin-induced diabetic apolipoprotein E (Apoe) knockout (KO) and At 2 r (also known as Agtr2)/Apoe double-KO (DKO) mice. Control and diabetic Apoe-KO mice received an AT2R antagonist PD123319 (5 mg kg−1 day−1) via osmotic minipump for 20 weeks (n = 7–8 per group).

Results

Diabetes was associated with a sixfold increase in plaque area (diabetic Apoe-KO: 12.7 ± 1.4% vs control Apoe-KO: 2.3 ± 0.4%, p < 0.001) as well as a significant increase in aortic expression of the gene At 2 r (also known as Agtr2). The increase in plaque area with diabetes was attenuated in AT2R antagonist-treated diabetic Apoe-KO mice (7.1 ± 0.5%, p < 0.05) and in diabetic At 2 r/Apoe DKO mice (9.2 ± 1.3%, p < 0.05). These benefits occurred independently of glycaemic control or BP, and were associated with downregulation of a range of pro-inflammatory cytokines, adhesion molecules, chemokines and various extracellular matrix proteins.

Conclusions/interpretation

This study provides evidence for AT2R playing a role in the development of diabetes-associated atherosclerosis. These findings suggest a potential utility of AT2R blockers in the prevention and treatment of diabetic macrovascular complications.
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Metadata
Title
Angiotensin II subtype 2 receptor blockade and deficiency attenuate the development of atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes
Authors
A. Koïtka
Z. Cao
P. Koh
A. M. D. Watson
K. C. Sourris
L. Loufrani
A. Soro-Paavonen
T. Walther
K. J. Woollard
K. A. M. Jandeleit-Dahm
M. E. Cooper
T. J. Allen
Publication date
01-03-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 3/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1619-x

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