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

AI Article Synopsis

  • Patients with diabetes face issues in forming new blood vessels, which worsens tissue oxygen supply in heart and legs due to atherosclerosis.
  • Researchers found 10 new insulin-regulated genes, including CITED2, that are negatively affecting these blood vessels by interfering with HIF signaling, crucial for new blood vessel formation.
  • Increased levels of CITED2 in diabetic mice and human tissue hinder blood vessel growth, while reducing CITED2 promotes vessel formation, highlighting its role in diabetes-related vascular complications.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127242PMC
http://dx.doi.org/10.2337/db16-0001DOI Listing

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