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 R. Preil, Hans Christian Beck, Sally L. Dunwoodie, Michael T. Watkins, Lars Melholt Rasmussen, Rask Madsen Christian

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 themAdm, Cited2, andCtgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxiainducible 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 control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb 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 proangiogenic function.

Original languageEnglish (US)
Pages (from-to)3680-3690
Number of pages11
JournalDiabetes
Volume65
Issue number12
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Fingerprint

Trans-Activators
Tail
Down-Regulation
Endothelial Cells
Insulin
Type 2 Diabetes Mellitus
Diabetes Complications
Femoral Artery
Vascular Resistance
Genes
Ligation
Blood Vessels
Insulin Resistance
Lower Extremity
Myocardium
Up-Regulation
Extremities
Perfusion
Obesity
Cell Proliferation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Wang, X., Lockhart, S. M., Rathjen, T., Albadawi, H., Sørensen, D., O'neill, B. T., ... Christian, R. M. (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

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; Preil, Simone R.; Beck, Hans Christian; Dunwoodie, Sally L.; Watkins, Michael T.; Rasmussen, Lars Melholt; Christian, Rask Madsen.

In: Diabetes, Vol. 65, No. 12, 01.12.2016, p. 3680-3690.

Research output: Contribution to journalArticle

Wang, X, Lockhart, SM, Rathjen, T, Albadawi, H, Sørensen, D, O'neill, BT, Dwivedi, N, Preil, SR, Beck, HC, Dunwoodie, SL, Watkins, MT, Rasmussen, LM & Christian, RM 2016, 'Insulin downregulates the transcriptional coregulator cited2, an inhibitor of proangiogenic function in endothelial cells', Diabetes, vol. 65, no. 12, pp. 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 ; Preil, Simone R. ; Beck, Hans Christian ; Dunwoodie, Sally L. ; Watkins, Michael T. ; Rasmussen, Lars Melholt ; Christian, Rask Madsen. / Insulin downregulates the transcriptional coregulator cited2, an inhibitor of proangiogenic function in endothelial cells. In: Diabetes. 2016 ; Vol. 65, No. 12. pp. 3680-3690.
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