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Urotensin II Receptor Antagonism Confers Vasoprotective Effects in Diabetes Associated Atherosclerosis: Studies in Humans and in a Mouse Model of Diabetes

Urotensin II Receptor Antagonism Confers Vasoprotective Effects in Diabetes Associated Atherosclerosis: Studies in Humans and in a Mouse Model of Diabetes

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

Diabetologia. 2013 May;56(5):1155-65.

PMID: 23344731

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP474960446	SB 657510		474960-44-6	Price

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