Deacetylation of MnSOD by PARP-regulated SIRT3 protects retinal capillary endothelial cells from hyperglycemia-induced damage
Deacetylation of MnSOD by PARP-regulated SIRT3 protects retinal capillary endothelial cells from hyperglycemia-induced damage
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DOI：
10.1016/j.bbrc.2015.12.037
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发表时间：
2016-04-08
影响因子：
3.1
通讯作者：
Xu, Xun
中科院分区：
文献类型：
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作者：
Gao, Jian;Zheng, Zhi;Xu, Xun
糖尿病视网膜病变发展中的一个关键起始点被认为是视网膜线粒体中活性氧（ROS）的产生，并且它们的清除酶锰超氧化物歧化酶（MnSOD）受到损害。然而，高葡萄糖调节MnSOD的机制尚不清楚。在这项研究中，我们发现，高浓度的葡萄糖抑制组蛋白去乙酰化酶SIRT 3的表达，这导致在牛视网膜毛细血管内皮细胞和糖尿病大鼠视网膜中的MnSOD活性降低。相反，SIRT 3过表达通过去乙酰化和激活MnSOD来减轻高血糖应激。此外，高血糖诱导的SIRT 3下调涉及聚（ADP-核糖）聚合酶（PARP）的激活。我们的研究首次将PARP调节的SIRT 3对MnSOD的脱乙酰化与糖尿病视网膜病变的发病机制联系起来。了解SIRT 3在糖尿病视网膜病变发病机制中的作用有助于阐明未来药物干预的关键分子靶点。(C)2016 Elsevier Inc. All rights reserved.
A key initiator in the development of diabetic retinopathy is considered to be the production of reactive oxygen species (ROS) in the retinal mitochondria, and their scavenging enzyme, manganese superoxide dismutase (MnSOD), is compromised. However, the mechanism by which high glucose regulates MnSOD is unclear. In this study, we found that a high concentration of glucose inhibited the expression of the histone deacetylase SIRT3, which resulted in a reduction in MnSOD activity in bovine retinal capillary endothelial cells and in the retinas of diabetic rats. Conversely, SIRT3 overexpression attenuated hyperglycemic stress through deacetylation and activation of MnSOD. Furthermore, the hyperglycemia induced downregulation of SIRT3 involved the activation of poly (ADP-ribose) polymerase (PARP). Our study is the first to link the deacetylation of MnSOD by PARP-regulated SIRT3 with the pathogenesis of diabetic retinopathy. Understanding the role of SIRT3 in the pathogenesis of diabetic retinopathy could help elucidate key molecular targets for future pharmacological interventions. (C) 2016 Elsevier Inc. All rights reserved.