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. 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.

Targeting CITED2 for Angiogenesis in Obesity and Insulin Resistance

“…In conclusion, data in the study by Wang et al (10) defines a group of endothelial genes, especially Cited2 , that may be dysregulated in insulin resistance and type 2 diabetes. The interaction of CITED2 and HIF1 impairs endothelial function and angiogenesis during the development and progression of CHD and peripheral vascular disease.…”

“…In this issue of Diabetes , Wang et al (10) investigated how insulin regulates CITED2 expression in endothelial cells and CITED2 expression in obese mouse models and patients with insulin resistance and type 2 diabetes. A total of 10 novel genes were identified to be involved in this insulin regulation, and 3 of them ( Adm , Cited2 , and Ctgf) were downregulated in endothelial cells through a forkhead box O1 (FoxO1) signaling pathway that may modulate angiogenesis in the context of insulin resistance.…”

“…The study by Wang et al (10) provides novel insights regarding interaction of CITED2 and HIF1 signaling in the regulation of endothelial function and angiogenesis in patients with diabetes. This is translationally relevant as therapeutic targeting of CITED2 has a potential application for the prevention of the impaired neovascular responses to ischemia in CHD and peripheral vascular disease in states of insulin resistance.…”

Down-regulated miR-145 rescues insulin resistance in endothelial cells

“…Correspondingly, miR-145 mimics obviously suppressed glycogen synthesis of IR models, whereas miR-145 inhibitor had the exact opposite effect on glycogen content (P<0.05, Figure 3B). As for the flow cytometry analysis, the apoptosis rate of IR models was raised evidently, which could be enhanced by overexpressed miR-145 and reversed by miR-145 inhibitor (P<0.05, Figure 3C diabetes mellitus, but also a key cause of endothelial cell injury [22]. IR interacts with endothelial cells injury, high-concentrations of insulin can disrupt cell signaling pathways and make cells insensitive to insulin, leading to endothelial dysfunction [23].…”

CITED Proteins in the Heart of Pluripotent Cells and in Heart’s Full Potential

“…In addition, CITED2 interacts with the acetyltransferase GCN5 and under fasting conditions, CITED2 promotes PGC-1ɑ activation in response to glucagon by inhibiting the acetylation of PGC-1ɑ by GCN5 [73]. [3,7,64,72,[78][79][80][81][82][83][84][85][86][87]. In addition, FoxP1, as well as other transcription factors required for the maintenance of pluripotency, stimulate the expression of Cited2 in mouse ESC [88].…”