Thioredoxin Interacting Protein (TXNIP) Induces Inflammation Through Chromatin Modification in Retinal Capillary Endothelial Cells Under Diabetic Conditions
Thioredoxin Interacting Protein (TXNIP) Induces Inflammation Through Chromatin Modification in Retinal Capillary Endothelial Cells Under Diabetic Conditions
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DOI：
10.1002/jcp.21852
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发表时间：
2009-10-01
影响因子：
5.6
通讯作者：
Singh, Lalit P.
中科院分区：
文献类型：
--
作者：
Perrone, Lorena;Devi, Takhellambam S.;Singh, Lalit P.
慢性高血糖和晚期糖基化终产物受体（RAGE）的激活是糖尿病视网膜病变微血管疾病发展的已知危险因素。硫氧还蛋白相互作用蛋白（TXNIP）是一种内源性抗氧化硫氧还蛋白（TRX）抑制剂，在糖尿病及其血管并发症中起诱发作用。本文研究HG和RAGE是否通过激活TXNIP诱导糖尿病大鼠视网膜内皮细胞（EC）炎症，以及表观遗传机制是否在炎症基因表达中发挥作用。我们发现RAGE通过其配体S100B或HG处理视网膜EC激活可诱导TXNIP和炎症基因如Cox2、VEGF-A和ICAMI的表达。siRNA沉默TXNIP可抑制PAGE和HG效应，而在EC中稳定过表达人TXNIP cDNA可提高炎症水平。p38 MAPK-NF-kappa B信号通路和组蛋白H3赖氨酸(K) 9修饰参与了txnip诱导的炎症。染色质免疫沉淀（ChIP）实验显示，在EC中，TXNIP的过表达消除了基因失活标记H3K9三甲基化，并增加了携带nf - κ b结合位点的近端Cox2启动子的H3K9乙酰化，这是基因诱导的指标。这些发现对于理解糖尿病视网膜病变中眼炎症和内皮功能障碍的分子机制具有重要意义。j .细胞。中国生物医学工程学报，21(2):557 - 557,2009。(C) 2009 Wiley-Liss, Inc。
Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF-A, and ICAMI. TXNIP silencing by siRNA impedes PAGE and HG effects while stable over-expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK-NF-kappa B signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP-induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over-expression in EC abolishes H3K9 tri-methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF-kappa B-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy. J. Cell. Physiol. 221: 262-272, 2009. (C) 2009 Wiley-Liss, Inc.