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 - Preil, Simone R.
AU - Beck, Hans Christian
AU - Dunwoodie, Sally L.
AU - Watkins, Michael T.
AU - Rasmussen, Lars Melholt
AU - Christian, Rask Madsen
N1 - Publisher Copyright:
©2016 by the American Diabetes Association.
PY - 2016/12/1
Y1 - 2016/12/1
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 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=85000783284&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85000783284&partnerID=8YFLogxK
U2 - 10.2337/db16-0001
DO - 10.2337/db16-0001
M3 - Article
C2 - 27561725
AN - SCOPUS:85000783284
SN - 0012-1797
VL - 65
SP - 3680
EP - 3690
JO - Diabetes
JF - Diabetes
IS - 12
ER -