GATA4 protects against hyperglycemia‑induced endothelial dysfunction by regulating NOX4 transcription

Xu,Hongfei; Wang,Zhen; Sun,Zewei; Ni,Yiming; Zheng,Liangrong

doi:10.3892/mmr.2017.8062

GATA4 protects against hyperglycemia‑induced endothelial dysfunction by regulating NOX4 transcription

Authors:
- Hongfei Xu
- Zhen Wang
- Zewei Sun
- Yiming Ni
- Liangrong Zheng
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Affiliations: Department of Cardiothoracic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: November 14, 2017 https://doi.org/10.3892/mmr.2017.8062
Pages: 1485-1492
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Endothelial dysfunction is one of the most common complications associated with diabetes and may lead to atherosclerosis. Conflicting reports indicate that NADPH oxidase 4 (NOX4) induces hydrogen peroxide production and cytotoxicity, but also has a protective effect on endothelial dysfunction. The present study aimed to identify the transcription factor responsible for NOX4 expression using a transcription factor activation profiling plate array and chromatin immunoprecipitation. Data from these analyses indicated that GATA‑binding protein 4 (GATA4) was able to mediate NOX4 transcription and is downregulated in human umbilical vein endothelial cells (HUVECs) that were exposed to hyperglycemic conditions as well as in the endothelial cells of a mouse diabetes model. Overexpression of GATA4 was demonstrated to lead to increased expression of NOX4 mRNA and protein. Furthermore, GATA4 overexpression resulted in increased nitric oxide (NO) production through the upregulation of endothelial NO synthase phosphorylation. Treatment with simvastatin, a drug known to preserve endothelial function through an unknown mechanism, improved endothelial cell function by upregulating GATA4 expression in HUVECs exposed to hyperglycemia. Results from these experiments demonstrated that GATA4 may inhibit diabetes‑induced endothelial dysfunction by acting as a transcription factor for NOX4 expression and increasing NO production. Thus, the present study revealed a novel molecular mechanism underlying endothelial dysfunction in diabetes and identified GATA4 as a potential therapeutic target.

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