Journal article
Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells
Diabetes (New York, N.Y.), Vol.65(12), pp.3680-3690
12/2016
DOI: 10.2337/db16-0001
PMCID: PMC5127242
PMID: 27561725
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. 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 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 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.
Details
- Title: Subtitle
- Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells
- Creators
- Xuanchun Wang - Joslin Diabetes Center and Harvard Medical School, Boston, MASamuel M Lockhart - Joslin Diabetes Center and Harvard Medical School, Boston, MAThomas Rathjen - Joslin Diabetes Center and Harvard Medical School, Boston, MAHassan Albadawi - Department of Surgery, Massachusetts General Hospital, Boston, MADitte Sørensen - Joslin Diabetes Center and Harvard Medical School, Boston, MABrian T O'Neill - Joslin Diabetes Center and Harvard Medical School, Boston, MANishant Dwivedi - Joslin Diabetes Center and Harvard Medical School, Boston, MASimone R Preil - Center for Individualized Medicine of Arterial Diseases (CIMA), Odense University Hospital, Odense, DenmarkHans Christian Beck - Center for Individualized Medicine of Arterial Diseases (CIMA), Odense University Hospital, Odense, DenmarkSally L Dunwoodie - Victor Chang Cardiac Research Institute, Sydney, New South Wales, AustraliaMichael T Watkins - Department of Surgery, Massachusetts General Hospital, Boston, MALars Melholt Rasmussen - Center for Individualized Medicine of Arterial Diseases (CIMA), Odense University Hospital, Odense, DenmarkChristian Rask-Madsen - Joslin Diabetes Center and Harvard Medical School, Boston, MA
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.65(12), pp.3680-3690
- Publisher
- American Diabetes Association
- DOI
- 10.2337/db16-0001
- PMID
- 27561725
- PMCID
- PMC5127242
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Grant note
- ; K08DK100543 / ; R21CA185196 / ; U24 DK076169 / ;
- Language
- English
- Date published
- 12/2016
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094491702771
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