骨桥蛋白
福克斯O1
内科学
染色质免疫沉淀
内分泌学
基因敲除
电泳迁移率测定
化学
下调和上调
蛋白激酶B
细胞生物学
发起人
生物
炎症
基因表达
巨噬细胞极化
磷酸化
医学
基因
生物化学
作者
Qiongge Zhang,Chaoqun Wang,Yehua Tang,Qiangqiang Zhu,Yongcheng Li,Haiyan Chen,Yi Bao,Song Xue,Liang-liang Sun,Wei Tang,Xiangfang Chen,Yong-quan Shi,Lefeng Qu,Bin Lu,Jiaoyang Zheng
摘要
Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE −/− mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt −1918 ~ −713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.
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