The role and underlying mechanism of CITED2-mediated insulin signaling pathway in the pathogenesis of diabetic vascular diseases

Abstract

It is well established that cardiovascular diseases are the leading causes of diabetes-related death. Endothelial dysfunction is widely accepted as the initial and critical factor contributing to diabetic vascular diseases. Insulin resistance may result in vascular endothelial dysfunction, which in turn aggravates diabetic vascular diseases. Via PI3K/Akt signaling pathway, insulin inhibits the function of FoxOs, which, endothelial FoxO1 especially, exerts an important role in atherosclerosis and angiogenesis. In this regard, Wang et al. characterized 10 FoxO1 target genes regulated by insulin in endothelial cells, among which, CITED2, a transcriptional coregulator, was selected to extensively investigate its role and the underlying mechanism of insulin-regulated angiogenesis. CITED2 was significantly increased in vascular endothelial cells in diet-induced mice, ob/ob mice, as well as obese type 2 diabetic patients, all of those models or subjects are accompanied by insulin resistance. In endothelial cells, insulin significantly down-regulated CITED2 expression through insulin receptor-PI3K-Akt-FoxO1 pathway. Inhibition of CITED2 resulted in significant increases in proliferation and tube formation of endothelial cells. Overexpression of CITED2, however, repressed the transactivation of HIF. The study on the mouse model with hind limb ischemia showed that endothelial CITED2 deficiency gave rise to significant increases of expression of endothelin-1, a well-known HIF target gene, induced by ischemia or hypoxia, suggesting that CITED2 inhibited endothelial angiogenesis via suppressing HIF transactivation. In summary, insulin resistance accompanying obesity and type 2 diabetes leads to enhanced CITED2 expression, consequently impairing HIF signaling and proangiogenic capacity in endothelial cells. Inhibition of CITED2 will be a promising novel way to deal with ischemic cardiovascular diseases in diabetic patients. (Chin J Endocrinol Metab, 2017, 33: 637-643) Key words: Endothelial cell; Insulin signaling pathway; FoxO1; CITED2; Angiogenesis