Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis

Studies in humans and in a mouse model of diabetes

Anna Watson, Murat Olukman, Christine Koulis, Yugang Tu, D Samijono, Derek Y C Yuen, C Lee, David Behm, Mark Cooper, Karin Agnes Maria Jandeleit-Dahm, A C Calkin, Terri J Allen

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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.
Original languageEnglish
Pages (from-to)1155 - 1165
Number of pages11
JournalDiabetologia
Volume56
Issue number5
DOIs
Publication statusPublished - 2013

Cite this

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. / Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis : Studies in humans and in a mouse model of diabetes. In: Diabetologia. 2013 ; Vol. 56, No. 5. pp. 1155 - 1165.
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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.",
author = "Anna Watson and Murat Olukman and Christine Koulis and Yugang Tu and D Samijono and Yuen, {Derek Y C} and C Lee and David Behm and Mark Cooper and Jandeleit-Dahm, {Karin Agnes Maria} and Calkin, {A C} and Allen, {Terri J}",
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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 journalArticleResearchpeer-review

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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

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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.

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U2 - 10.1007/s00125-013-2837-9

DO - 10.1007/s00125-013-2837-9

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JO - Diabetologia

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SN - 0012-186X

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