Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells

Xuanchun Wang, Samuel M Lockhart, Thomas Rathjen, Hassan Albadawi, Ditte Sørensen, Brian T O'Neill, Nishant Dwivedi, Simone Rørdam Preil, Hans Christian Beck, Sally L Dunwoodie, Michael T Watkins, Lars Melholt Rasmussen, Christian Rask-Madsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2 and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CITED2, which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than non-diabetic controls. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation while CITED2 overexpression impaired HIF activity in vitro After femoral artery ligation, induction of an endothelial-specific HIF target gene in hindlimb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2 which impairs HIF signaling and endothelial pro-angiogenic function.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind65
Udgave nummer12
Sider (fra-til)3680-3690
ISSN0046-0192
DOI
StatusUdgivet - 2016

Fingeraftryk

Down-Regulation
Insulin
Type 2 Diabetes Mellitus
Diabetes Complications
Femoral Artery
Ligation
Insulin Resistance
Myocardium
Up-Regulation
Perfusion
Cell Proliferation
Diet
Muscles

Citer dette

Wang, X., Lockhart, S. M., Rathjen, T., Albadawi, H., Sørensen, D., O'Neill, B. T., ... Rask-Madsen, C. (2016). Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells. Diabetes, 65(12), 3680-3690. https://doi.org/10.2337/db16-0001
Wang, Xuanchun ; Lockhart, Samuel M ; Rathjen, Thomas ; Albadawi, Hassan ; Sørensen, Ditte ; O'Neill, Brian T ; Dwivedi, Nishant ; Rørdam Preil, Simone ; Beck, Hans Christian ; Dunwoodie, Sally L ; Watkins, Michael T ; Rasmussen, Lars Melholt ; Rask-Madsen, Christian. / Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells. I: Diabetes. 2016 ; Bind 65, Nr. 12. s. 3680-3690.
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title = "Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells",
abstract = "In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2 and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CITED2, which was downregulated by insulin by up to 54{\%}, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than non-diabetic controls. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation while CITED2 overexpression impaired HIF activity in vitro After femoral artery ligation, induction of an endothelial-specific HIF target gene in hindlimb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2 which impairs HIF signaling and endothelial pro-angiogenic function.",
author = "Xuanchun Wang and Lockhart, {Samuel M} and Thomas Rathjen and Hassan Albadawi and Ditte S{\o}rensen and O'Neill, {Brian T} and Nishant Dwivedi and {R{\o}rdam Preil}, Simone and Beck, {Hans Christian} and Dunwoodie, {Sally L} and Watkins, {Michael T} and Rasmussen, {Lars Melholt} and Christian Rask-Madsen",
note = "{\circledC} 2016 by the American Diabetes Association.",
year = "2016",
doi = "10.2337/db16-0001",
language = "English",
volume = "65",
pages = "3680--3690",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
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Wang, X, Lockhart, SM, Rathjen, T, Albadawi, H, Sørensen, D, O'Neill, BT, Dwivedi, N, Rørdam Preil, S, Beck, HC, Dunwoodie, SL, Watkins, MT, Rasmussen, LM & Rask-Madsen, C 2016, 'Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells', Diabetes, bind 65, nr. 12, s. 3680-3690. https://doi.org/10.2337/db16-0001

Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells. / Wang, Xuanchun; Lockhart, Samuel M; Rathjen, Thomas; Albadawi, Hassan; Sørensen, Ditte; O'Neill, Brian T; Dwivedi, Nishant; Rørdam Preil, Simone; Beck, Hans Christian; Dunwoodie, Sally L; Watkins, Michael T; Rasmussen, Lars Melholt; Rask-Madsen, Christian.

I: Diabetes, Bind 65, Nr. 12, 2016, s. 3680-3690.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells

AU - Wang, Xuanchun

AU - Lockhart, Samuel M

AU - Rathjen, Thomas

AU - Albadawi, Hassan

AU - Sørensen, Ditte

AU - O'Neill, Brian T

AU - Dwivedi, Nishant

AU - Rørdam Preil, Simone

AU - Beck, Hans Christian

AU - Dunwoodie, Sally L

AU - Watkins, Michael T

AU - Rasmussen, Lars Melholt

AU - Rask-Madsen, Christian

N1 - © 2016 by the American Diabetes Association.

PY - 2016

Y1 - 2016

N2 - In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2 and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CITED2, which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than non-diabetic controls. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation while CITED2 overexpression impaired HIF activity in vitro After femoral artery ligation, induction of an endothelial-specific HIF target gene in hindlimb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2 which impairs HIF signaling and endothelial pro-angiogenic function.

AB - In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2 and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CITED2, which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than non-diabetic controls. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation while CITED2 overexpression impaired HIF activity in vitro After femoral artery ligation, induction of an endothelial-specific HIF target gene in hindlimb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2 which impairs HIF signaling and endothelial pro-angiogenic function.

U2 - 10.2337/db16-0001

DO - 10.2337/db16-0001

M3 - Journal article

VL - 65

SP - 3680

EP - 3690

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 12

ER -