浙江大学医学院戴海斌研究小组发现，内皮组蛋白去乙酰化酶9通过调节内皮-间质转化促进小鼠糖尿病视网膜病变。相关论文于2025年3月31日发表在《中国药理学报》杂志上。

在这项研究中，课题组人员研究了HDAC9在DR中的关键作用及其潜在机制。连续5 d注射链脲佐菌素（STZ, 50mg/kg）建立小鼠DR模型。造模12周后定期监测血糖，进行DR实验。该课题组发现HDAC9在糖尿病患者玻璃体液和DR模型小鼠视网膜内皮细胞中的表达水平显著升高。在体内，内皮细胞HDAC9敲低可减少EndoMT，减轻DR病理，而在DR模型小鼠中，HDAC9过表达可加重EndoMT。

为了阐明HDAC9与DR相关的下游靶基因，该课题组研究人员对stz诱导的视网膜病变进行了ChIP-seq和RNA-seq综合分析，确定HDAC9参与了膜联蛋白A2 （ANXA2）的转录调控。该研究团队证实HDAC9与ANXA2的启动子区结合，导致高糖处理的人视网膜微血管内皮细胞和stz诱导的DR模型小鼠中ANXA2的表达下调。过表达ANXA2可显著降低stz诱导的DR模型小鼠的EndoMT过程。

总的来说，他们的研究结果表明，HDAC9通过调节ANXA2转录来促进EndoMT，从而破坏DR期间的血管稳态。本研究揭示了HDAC9和ANXA2在DR病理中的作用，为针对DR的潜在治疗策略提供了理论基础。

据了解，糖尿病视网膜病变（DR）是糖尿病的一种常见和特殊的微血管并发症，也是导致工作年龄成人失明的主要原因。内皮-间充质转化（EndoMT）是多种慢性血管疾病的基础，而组蛋白去乙酰化酶9 （HDAC9）参与心脑血管疾病、自身免疫性疾病和乳腺癌的病理过程。最近的证据表明，HDAC9促进EndoMT，从而影响动脉粥样硬化疾病的进展。

附：英文原文

Title: Endothelial histone deacetylase 9 promotes diabetic retinopathy in mice by regulating endothelial–mesenchymal transition

Author: Bei, Yun, Shen, Ze-xu, Lin, Hao-ran, Wei, Tao-feng, Wang, Yi-hao, Su, Zhi-tao, Dai, Yun-jian, Wang, Yan-hong, Huang, Ling-ling, Zhu, Tao, Hu, Wei, Ye, Juan, Wu, Gong-xiong, Dai, Hai-bin

Issue&Volume: 2025-03-31

Abstract: Diabetic retinopathy (DR) is a common and specific microvascular complication of diabetes and the leading cause of blindness in working-age adults. Endothelial-mesenchymal transition (EndoMT) underlies various chronic vascular diseases, while histone deacetylase 9 (HDAC9) is involved in the pathological process of cardiovascular diseases, cerebrovascular diseases, autoimmune diseases, and breast cancer. Recent evidence has shown that HDAC9 promotes EndoMT, thereby affecting the progression of atherosclerotic disease. In this study, we investigated the critical role of HDAC9 in DR and the underlying mechanism. DR model was established in mice by injecting streptozotocin (STZ, 50mg/kg) for 5 consecutive days. Blood glucose was monitored regularly and DR experiments were performed 12 weeks after modeling. We showed that the expression levels of HDAC9 were significantly elevated in the vitreous fluid of diabetic patients and the retinal endothelial cells of DR model mice. Knockdown of endothelial HDAC9 reduced EndoMT and alleviated DR pathology in vivo, whereas overexpression of HDAC9 exacerbated EndoMT in DR model mice. To elucidate the downstream target genes of HDAC9 implicated in DR, we conducted integrated ChIP-seq and RNA-seq analysis of the retina in STZ-induced retinopathy and established that HDAC9 was involved in the transcriptional regulation of annexin A2 (ANXA2). We demonstrated that HDAC9 was bound to the promoter region of ANXA2, leading to the downregulation of ANXA2 expression in high glucose-treated human retinal microvascular endothelial cells and STZ-induced DR model mice. Overexpression of ANXA2 significantly reduced the EndoMT process in STZ-induced DR model mice. Collectively, our results demonstrate that HDAC9 promotes EndoMT by regulating ANXA2 transcription, thereby disrupting vascular homeostasis during DR. This study sheds light on the roles of HDAC9 and ANXA2 in DR pathology and provides a theoretical foundation for the potential therapeutic strategies to target DR.

DOI: 10.1038/s41401-025-01523-9

Source: https://www.nature.com/articles/s41401-025-01523-9