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.
Mol Med Rep. 2018 Jan;17(1):1485-1492. doi: 10.3892/mmr.2017.8062. Epub 2017 Nov 14.
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.
内皮功能障碍是与糖尿病相关的最常见并发症之一，可能导致动脉粥样硬化。相互矛盾的报告表明，烟酰胺腺嘌呤二核苷酸磷酸氧化酶 4（NOX4）可诱导过氧化氢的产生和细胞毒性，但对内皮功能障碍也具有保护作用。本研究旨在使用转录因子激活谱板阵列和染色质免疫沉淀来鉴定负责 NOX4 表达的转录因子。这些分析的数据表明，GATA 结合蛋白 4（GATA4）能够介导 NOX4 转录，并且在暴露于高血糖条件下的人脐静脉内皮细胞（HUVEC）以及在小鼠糖尿病模型的内皮细胞中下调。过表达 GATA4 导致 NOX4 mRNA 和蛋白的表达增加。此外，通过上调内皮型一氧化氮合酶磷酸化，GATA4 过表达导致一氧化氮（NO）产生增加。用辛伐他汀（一种通过未知机制来保护内皮功能的药物）进行治疗可通过上调高血糖暴露的 HUVEC 中的 GATA4 表达来改善内皮细胞功能。这些实验的结果表明，GATA4 可能通过作为 NOX4 表达的转录因子并增加 NO 产生来抑制糖尿病引起的内皮功能障碍。因此，本研究揭示了糖尿病内皮功能障碍的新分子机制，并确定 GATA4 为潜在的治疗靶标。
