Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1155 - 1165 |
| Number of pages | 11 |
| Journal | Diabetologia |
| Volume | 56 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2013 |
Cite this
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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. / Watson, Anna; Olukman, Murat; Koulis, Christine; Tu, Yugang; Samijono, D; Yuen, Derek Y C; Lee, C; Behm, David; Cooper, Mark; Jandeleit-Dahm, Karin Agnes Maria; Calkin, A C; Allen, Terri J.
In: Diabetologia, Vol. 56, No. 5, 2013, p. 1155 - 1165.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis
T2 - Studies in humans and in a mouse model of diabetes
AU - Watson, Anna
AU - Olukman, Murat
AU - Koulis, Christine
AU - Tu, Yugang
AU - Samijono, D
AU - Yuen, Derek Y C
AU - Lee, C
AU - Behm, David
AU - Cooper, Mark
AU - Jandeleit-Dahm, Karin Agnes Maria
AU - Calkin, A C
AU - Allen, Terri J
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://link.springer.com/article/10.1007%2Fs00125-013-2837-9
U2 - 10.1007/s00125-013-2837-9
DO - 10.1007/s00125-013-2837-9
M3 - Article
VL - 56
SP - 1155
EP - 1165
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 5
ER -