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01.05.2013 | Article

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

verfasst von: A. M. D. Watson, M. Olukman, C. Koulis, Y. Tu, D. Samijono, D. Yuen, C. Lee, D. J. Behm, M. E. Cooper, K. A. M. Jandeleit-Dahm, A. C. Calkin, T. J. Allen

Erschienen in: Diabetologia | Ausgabe 5/2013

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Abstract

Aims/hypothesis

The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed.

Methods

Endothelial cells were grown in normal- and high-glucose (5 and 25 mmol/l) media with and without UII (10⁻⁸ mol/l) and/or the UII receptor antagonist, SB-657510 (10⁻⁸ mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mg kg⁻¹ day⁻¹; n = 20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated.

Results

In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1.

Conclusions/interpretation

This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.

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Titel: Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes
verfasst von: A. M. D. Watson
M. Olukman
C. Koulis
Y. Tu
D. Samijono
D. Yuen
C. Lee
D. J. Behm
M. E. Cooper
K. A. M. Jandeleit-Dahm
A. C. Calkin
T. J. Allen
Publikationsdatum: 01.05.2013
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 5/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-2837-9

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