Gene interactions and pathways from curated databases and text-mining
PloS one 2012, PMID: 23144758

NADPH oxidase 4 mediates insulin-stimulated HIF-1α and VEGF expression, and angiogenesis in vitro.

Meng, Dan; Mei, Aihong; Liu, Junxu; Kang, Xueling; Shi, Xianglin; Qian, Ruizhe; Chen, Sifeng

Acute intensive insulin therapy causes a transient worsening of diabetic retinopathy in type 1 diabetes patients and is related to VEGF expression. Reactive oxygen species (ROS) have been shown to be involved in HIF-1α and VEGF expression induced by insulin, but the role of specific ROS sources has not been fully elucidated. In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin-stimulated HIF-1α and VEGF expression, and angiogenic responses in human microvascular endothelial cells (HMVECs). Here we demonstrate that knockdown of Nox4 by siRNA reduced insulin-stimulated ROS generation, the tyrosine phosphorylation of IR-β and IRS-1, but did not change the serine phosphorylation of IRS-1. Nox4 gene silencing had a much greater inhibitory effect on insulin-induced AKT activation than ERK1/2 activation, whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP. Inhibition of Nox4 expression inhibited the transcriptional activity of VEGF through HIF-1. Overexpression of wild-type Nox4 was sufficient to increase VEGF transcriptional activity, and further enhanced insulin-stimulated the activation of VEGF. Downregulation of Nox4 expression decreased insulin-stimulated mRNA and protein expression of HIF-1α, but did not change the rate of HIF-1α degradation. Inhibition of Nox4 impaired insulin-stimulated VEGF expression, cell migration, cell proliferation, and tube formation in HMVECs. Our data indicate that Nox4-derived ROS are essential for HIF-1α-dependent VEGF expression, and angiogenesis in vitro induced by insulin. Nox4 may be an attractive therapeutic target for diabetic retinopathy caused by intensive insulin treatment.

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Text Mining Data

VEGF → insulin: " NADPH oxidase 4 mediates insulin stimulated HIF-1a and VEGF expression, and angiogenesis in vitro "

VEGF → NADPH oxidase 4: " NADPH oxidase 4 mediates insulin stimulated HIF-1a and VEGF expression, and angiogenesis in vitro "

HIF-1a → insulin: " NADPH oxidase 4 mediates insulin stimulated HIF-1a and VEGF expression, and angiogenesis in vitro "

HIF-1a → NADPH oxidase 4: " NADPH oxidase 4 mediates insulin stimulated HIF-1a and VEGF expression, and angiogenesis in vitro "

VEGF → insulin: " Reactive oxygen species ( ROS ) have been shown to be involved in HIF-1a and VEGF expression induced by insulin , but the role of specific ROS sources has not been fully elucidated "

HIF-1a → insulin: " Reactive oxygen species ( ROS ) have been shown to be involved in HIF-1a and VEGF expression induced by insulin , but the role of specific ROS sources has not been fully elucidated "

VEGF ⊣ NADPH oxidase subunit 4 (Nox4): " In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin stimulated HIF-1a and VEGF expression, and angiogenic responses in human microvascular endothelial cells ( HMVECs ) "

HIF-1a ⊣ NADPH oxidase subunit 4 (Nox4): " In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin stimulated HIF-1a and VEGF expression, and angiogenic responses in human microvascular endothelial cells ( HMVECs ) "

VEGF → insulin: " In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin stimulated HIF-1a and VEGF expression, and angiogenic responses in human microvascular endothelial cells ( HMVECs ) "

HIF-1a → insulin: " In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin stimulated HIF-1a and VEGF expression, and angiogenic responses in human microvascular endothelial cells ( HMVECs ) "

AKT → insulin: " Nox4 gene silencing had a much greater inhibitory effect on insulin induced AKT activation than ERK1/2 activation, whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP "

VEGF → Nox4: " Inhibition of Nox4 expression inhibited the transcriptional activity of VEGF through HIF-1 "

VEGF ⊣ Nox4: " Overexpression of wild-type Nox4 was sufficient to increase VEGF transcriptional activity, and further enhanced insulin stimulated the activation of VEGF "

VEGF → insulin: " Inhibition of Nox4 impaired insulin stimulated VEGF expression, cell migration, cell proliferation, and tube formation in HMVECs "

VEGF → Nox4: " Inhibition of Nox4 impaired insulin stimulated VEGF expression, cell migration, cell proliferation, and tube formation in HMVECs "

VEGF → HIF-1a: " Our data indicate that Nox4 derived ROS are essential for HIF-1a dependent VEGF expression, and angiogenesis in vitro induced by insulin "

VEGF → insulin: " Our data indicate that Nox4 derived ROS are essential for HIF-1a dependent VEGF expression, and angiogenesis in vitro induced by insulin "

Manually curated Databases

No curated data.