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

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.

• Authors: 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
• Journal: Diabetologia (Diabetologia) Vol. 56 Issue 5 Pg. 1155-65 (May 2013) ISSN: 1432-0428 [Electronic] Germany
• PMID: 23344731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protective Agents
• Receptors, G-Protein-Coupled
• SB 657510
• Sulfonamides
• UTS2R protein, human
• Urotensins
• urotensin II receptor, mouse
• urotensin II

Topics

• Animals
• Aorta (drug effects, immunology, metabolism, pathology)
• Atherosclerosis (complications, metabolism, pathology, prevention & control)
• Cell Adhesion (drug effects)
• Cells, Cultured
• Crosses, Genetic
• Diabetes Mellitus, Type 1 (complications)
• Diabetic Angiopathies (immunology, metabolism, pathology, prevention & control)
• Endothelium, Vascular (drug effects, immunology, metabolism, pathology)
• Human Umbilical Vein Endothelial Cells (drug effects, immunology, metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (drug effects, immunology)
• Pilot Projects
• Protective Agents (pharmacology, therapeutic use)
• Receptors, G-Protein-Coupled (antagonists & inhibitors, metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Urotensins (antagonists & inhibitors, biosynthesis, metabolism)