骨桥蛋白在糖尿病血管并发症中的表达调控及作用机制研究

Vascular complications are responsible for most of the excess mutilation and mortality observed in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis of vascular complications, and enhanced expression of OPN was observed in plasma and atherosclerotic plaques from diabetes.Although hyperglycemia upregulates OPN levels, the regulation of OPN expression is not clear. Transcription factor FoxO1 is closely association with insulin resistance and diabetes. Hyperglycemia enhances the transcriptional activity of FoxO1 by inhibiting phosphorylation and promoting deacetylation of FoxO1. In our previous study we found that FoxO1 upregulates OPN expression in macrophage. We presume that hyperglycemia enhances the activity of FoxO1, by which upregulate the expression of OPN in vascular endothelial cell and macrophage, resulting in atherogenesis and serious vascular complications. Here we will investigate the regulation mechanism of OPN in vascular endothelial cell and macrophage mediated by FoxO1, and analyze the association between expression levels of FoxO1 and OPN in plasma and atherosclerotic lesion of diabetes. Our results will provide a new clue for the pathogenesis of diabetic vascular complication and a risk evaluation index.

血管并发症是糖尿病患者致残、致死的主要原因。骨桥蛋白（OPN）是血管并发症中动脉粥样斑块形成的重要因素，在糖尿病患者血浆和动脉斑块中表达增加，高血糖可促进OPN的表达,但其表达调控机制尚不清楚。FoxO1被认为与糖尿病胰岛素抵抗密切相关。高血糖可通过抑制FoxO1的磷酸化和促进去乙酰化而增强其转录活性, 我们前期研究发现转录因子FoxO1能够促进巨噬细胞中OPN的表达。因此，我们推测在糖尿病患者中高血糖通过激活FoxO1促进OPN的转录激活从而诱导动脉粥样斑块的形成，最终导致糖尿病严重的血管并发症。本课题将通过体内外实验探讨FoxO1基因在血管内皮细胞和巨噬细胞中对OPN的转录调控机制；并通过临床病理分析糖尿病患者中血浆和血管病变组织中FoxO1和OPN表达水平的相关性及其与血管病变程度的关系。研究结果有望为糖尿病血管并发症的发病机制提供新的线索和在临床上提供血管病变的风险评价指标。