AIM: To investigate the roles of a DNA methyltransferase(DNMT) inhibitor 5-aza-2'-deoxycytidine(5-aza-dC) in the regulation of antioxidant enzymes in diabetic retinopathy(DR) models. METHODS: DNMTs expressions and...AIM: To investigate the roles of a DNA methyltransferase(DNMT) inhibitor 5-aza-2'-deoxycytidine(5-aza-dC) in the regulation of antioxidant enzymes in diabetic retinopathy(DR) models. METHODS: DNMTs expressions and activity, and changes of two key antioxidant enzymes in DR, MnSOD(encoded by SOD2 gene) and glutathione S-transferase theta 1(GSTT1), were quantified in the isolated human retinal endothelial cells(HRECs) exposed to high glucose(HG) with or without 5-aza-dC treatment. The downstream exacerbating factors including vascular endothelial growth factor(VEGF), intercellular adhesion molecule 1(ICAM-1) and matrix metalloproteinase 2(MMP2), which are implicated in the pathogenesis of DR and closely related to oxidative stress were also analyzed. The key parameters were confirmed in the retina from streptozotocin(STZ) diabetic rats. RESULTS: DNMTs expression and DNMT activity was induced in HRECs exposed to HG. Hyperglycemia decreased MnSOD and GSTT1 expression. 5-aza-dC administration effectively suppressed DNMTs expression and activity and reversed the MnSOD and GSTT1 expression under HG condition. VEGF, ICAM-1 and MMP2 induced by HG were also suppressed by 5-aza-dC treatment. Similar results were observed in the retina from STZ diabetic rats. CONCLUSION: Our findings suggest that DNA methylation may serves as one of the mechanisms of antioxidant defense system disruption in DR progression. Modulation of DNA methylation using pharmaceutic means such as DNMT inhibitors could help maintain redox homeostasis and prevent further progression of DR.展开更多
内质网(endoplasmic reticulum,ER)是细胞内蛋白质折叠、Ca2+储存和脂质生物合成的重要部位。氧化应激、缺血、Ca2+稳态的失衡都可以引起ER内非折叠蛋白的聚集,通过ER内的分子伴侣激活非折叠蛋白反应(unfolded protein response,UPR)可...内质网(endoplasmic reticulum,ER)是细胞内蛋白质折叠、Ca2+储存和脂质生物合成的重要部位。氧化应激、缺血、Ca2+稳态的失衡都可以引起ER内非折叠蛋白的聚集,通过ER内的分子伴侣激活非折叠蛋白反应(unfolded protein response,UPR)可促进细胞的生存,但是过度ER应激(endoplasmic reticulum stress,ERS)可以诱导凋亡信号起始,通过线粒体依赖或者非线粒体依赖途径导致细胞死亡。因此,近年来ER被认为是决定细胞生存与凋亡的重要器官。最近研究提示,ERS在多种心血管疾病的病生理机制中起着重要作用,包括心功能不全及缺血性心脏疾病等。对这些疾病分子机制的进一步认识,将有助于开发新的靶向药物并治疗疾病。本文将对ERS和其与心血管疾病的关系进行综述。展开更多
基金Supported by the National Natural Science Foundation of China (No.81600757)Department of Science and Technology, Hunan (No.2015TP2007)
文摘AIM: To investigate the roles of a DNA methyltransferase(DNMT) inhibitor 5-aza-2'-deoxycytidine(5-aza-dC) in the regulation of antioxidant enzymes in diabetic retinopathy(DR) models. METHODS: DNMTs expressions and activity, and changes of two key antioxidant enzymes in DR, MnSOD(encoded by SOD2 gene) and glutathione S-transferase theta 1(GSTT1), were quantified in the isolated human retinal endothelial cells(HRECs) exposed to high glucose(HG) with or without 5-aza-dC treatment. The downstream exacerbating factors including vascular endothelial growth factor(VEGF), intercellular adhesion molecule 1(ICAM-1) and matrix metalloproteinase 2(MMP2), which are implicated in the pathogenesis of DR and closely related to oxidative stress were also analyzed. The key parameters were confirmed in the retina from streptozotocin(STZ) diabetic rats. RESULTS: DNMTs expression and DNMT activity was induced in HRECs exposed to HG. Hyperglycemia decreased MnSOD and GSTT1 expression. 5-aza-dC administration effectively suppressed DNMTs expression and activity and reversed the MnSOD and GSTT1 expression under HG condition. VEGF, ICAM-1 and MMP2 induced by HG were also suppressed by 5-aza-dC treatment. Similar results were observed in the retina from STZ diabetic rats. CONCLUSION: Our findings suggest that DNA methylation may serves as one of the mechanisms of antioxidant defense system disruption in DR progression. Modulation of DNA methylation using pharmaceutic means such as DNMT inhibitors could help maintain redox homeostasis and prevent further progression of DR.
