Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc
Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc
复制标题
DOI：
10.1016/j.ijcard.2018.04.082
复制
发表时间：
2018-10-01
影响因子：
3.5
通讯作者：
Cosentino, Francesco
中科院分区：
文献类型：
--
作者：
Costantino, Sarah;Paneni, Francesco;Cosentino, Francesco
目的：高血压诱导的活性氧（ROS）是心功能不全的关键介质。强化血糖控制（IGC）未能降低糖尿病患者心力衰竭的风险，但其潜在机制仍有待阐明。本研究调查是否表观遗传调节的促氧化剂适配器p66（Shc）有助于持续心肌功能障碍，尽管IGC.Methods和结果：p66（Shc）的表达增加，在糖尿病小鼠的心脏，和3周IGC缓释胰岛素植入物没有恢复这种现象。通过常规和二维斑点追踪超声心动图评估，持续的p66（Shc）上调与氧化应激、心肌炎症和左心室功能障碍相关。在IGC期间进行的p66（Shc）的体内基因沉默抑制ROS产生并恢复心脏功能。此外，我们发现甲基转移酶DNMT 3b和去乙酰化酶SIRT 1的失调导致p66（Shc）启动子上的CpG去甲基化和组蛋白3乙酰化，导致接头的持续转录。糖尿病心脏中DNMT 3b/SIRT 1轴的改变可通过miR-218和miR-34 a的上调来解释。事实上，在暴露于高葡萄糖的人类心肌细胞中，抑制这些miRNA恢复了DNMT 3b和SIRT 1的表达，并消除了p66（Shc）启动子上的不利表观遗传特征。一致地，重新编程miR-218和miR-34 a减弱了持续性p66（Shc）表达和ROS generation.Conclusions：在糖尿病左心室功能障碍中，连接miRNA和染色质修饰酶的复杂表观遗传机制驱动持续性p66（Shc）转录和ROS生成。我们的研究结果为药理学靶向表观遗传网络减轻糖尿病心肌病的临床负担奠定了基础。(c)2018爱思唯尔B. V.保留所有权利。
Aims: Hyperglycaemia-induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. Intensive glycaemic control (IGC) has failed to reduce risk of heart failure in patients with diabetes but the underlying mechanisms remain to be elucidated. The present study investigates whether epigenetic regulation of the pro-oxidant adaptor p66(Shc) contributes to persistent myocardial dysfunction despite IGC.Methods and results: p66(Shc) expression was increased in the heart of diabetic mice, and 3-week IGC by slow-release insulin implants did not revert this phenomenon. Sustained p66(Shc) upregulation was associated with oxidative stress, myocardial inflammation and left ventricular dysfunction, as assessed by conventional and 2D speckle-tracking echocardiography. In vivo gene silencing of p66(Shc), performed during IGC, inhibited ROS production and restored cardiac function. Furthermore, we show that dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 causes CpG demethylation and histone 3 acetylation on p66(Shc) promoter, leading to persistent transcription of the adaptor. Altered DNMT3b/SIRT1 axis in the diabetic heart was explained by upregulation of miR-218 and miR-34a. Indeed, in human cardiomyocytes exposed to high glucose, inhibition of these miRNAs restored the expression of DNMT3b and SIRT1 and erased the adverse epigenetic signatures on p66(Shc) promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66(Shc) expression and ROS generation.Conclusions: In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66(Shc) transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy. (c) 2018 Elsevier B.V. All rights reserved.