Insulin-induced activation of hypoxia-inducible factor-1 requires generation of reactive oxygen species by NADPH oxidase

被引:46
作者
Biswas, Sudipta
Gupta, Manveen Kaur
Chattopadhyay, Debasis
Mukhopadhyay, Chinmay K. [1 ]
机构
[1] Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi 110067, India
[2] Natl Ctr Genome Plant Res, New Delhi, India
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2007年 / 292卷 / 02期
关键词
reduced nicotinamide adenine dinucleotide phosphate oxidase; gene expression;
D O I
10.1152/ajpheart.00718.2006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Hypoxia-inducible factor ( HIF)-1 activation in response to hypoxia requires mitochondrial generation of reactive oxygen species ( ROS). In contrast, the requirement of ROS for HIF-1 activation by growth factors like insulin remains unexplored. To explore that, insulin-sensitive hepatic cell HepG2 or cardiac muscle cell H9c2 cells were pretreated with NADPH oxidase inhibitor diphenyleneiodonium chloride ( DPI) or apocynin and HIF-1 activation was tested by electrophoretic mobility shift and reporter gene assay. Antioxidants DPI or apocynin completely blocked insulin-stimulated HIF-1 activation. The restoration of HIF-1 activation by H2O2 in DPI-pretreated cells not only confirmed the role of ROS but also identified H2O2 as the responsible ROS. The role of NADPH oxidase was further confirmed by greater stimulation of HIF-1 during simultaneous treatment of suboptimal concentration of insulin along with NADPH but not by NADH. The role of oxidant generated by insulin is found to inhibit the protein tyrosine phosphatase as suggested by the following observations. First, tyrosine phosphatase-specific inhibitor sodium vanadate compensates DPI-inhibited HIF-1 activity. Second, sodium vanadate stimulates HIF-1 activation with suboptimal concentration of insulin. Third, DPI and pyrrolidene dithiocarbamate ( PDTC) blocks insulin-receptor tyrosine kinase activation. The activity of phosphatidylinositol 3-kinase as evidenced by Akt phosphorylation, involved in HIF-1 activation, is also dependent on ROS generation by insulin. Finally, DPI pretreatment blocked insulin-stimulated expression of genes like VEGF, GLUT1, and ceruloplasmin. Overall, our data provide strong evidence for the essential role of NADPH oxidase-generated ROS in insulin-stimulated activation of HIF-1.
引用
收藏
页码:H758 / H766
页数:9
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