作　　者： (王宣春）; (陈匡阳）; (李燕良）;

机构地区： 复旦大学附属华山医院内分泌科,上海200040

出　　处： 《中华内分泌代谢杂志》 2017年第8期637-643,共7页

摘　　要： 已知心血管病变是糖尿病致死的主要病因，内皮细胞功能紊乱被认为是糖尿病血管病变的始动和关键因素。胰岛素抵抗能够造成血管内皮功能紊乱，加速糖尿病血管病变的进展。胰岛素通过PI3K/Akt信号通路能够抑制FoxOs的功能，而内皮细胞FoxOs，特别是FoxO1，在动脉粥样硬化和血管新生过程中发挥重要功能。我们既往的工作发现了10个在血管内皮细胞中受胰岛素调控的FoxO1靶基因，重点研究了一个转录共调节因子-CITED2在胰岛素调控的血管新生过程中的作用和分子机制。在胰岛素抵抗的背景下，CITED2在饮食诱导的肥胖小鼠、ob/ob小鼠以及伴有肥胖的2型糖尿病患者血管内皮细胞中表达显著升高，而在内皮细胞中，胰岛素可通过胰岛素受体-PI3K-Akt-FoxO1信号通路显著下调CITED2的表达。抑制CITED2能够显著增加内皮细胞的增殖和血管形成能力，而过表达CITED2则能够抑制HIF的转录激活，后腿缺血动物模型研究发现，内皮细胞CITED2基因缺失导致缺血缺氧诱导的HIF靶基因内皮素-1的表达显著升高，提示CITED2通过抑制HIF的转录活性，抑制内皮细胞新生血管形成。综上所述，伴随肥胖和2型糖尿病的胰岛素抵抗引起CITED2的表达增加，导致内皮细胞HIF信号通路和血管新生能力受损，通过抑制内皮CITED2有望找到治疗糖尿病患者缺血性心血管疾病新的治疗方法。 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.

关 键 词： 内皮细胞 胰岛素信号通路 血管新生