Cardiology Unit, Department of Medicine Solna, Karolinska Institute & Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Cardiology, University of Zurich, University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
Clinic for Equine Internal Medicine, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
Int J Cardiol. 2018 Oct 1;268:179-186. doi: 10.1016/j.ijcard.2018.04.082. Epub 2018 Jun 30.
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 contributes to persistent myocardial dysfunction despite IGC.
p66 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 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, 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 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 promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66 expression and ROS generation.
In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66 transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy.
高血糖诱导的活性氧（ROS）是心脏功能障碍的关键介质。强化血糖控制（IGC）未能降低糖尿病患者心力衰竭的风险，但潜在机制仍有待阐明。本研究旨在探讨尽管进行了 IGC，氧化应激适应蛋白 p66 的表观遗传调节是否导致持续性心肌功能障碍。
糖尿病小鼠心脏中 p66 的表达增加，而通过缓释胰岛素植入进行 3 周的 IGC 并不能逆转这种现象。持续的 p66 上调与氧化应激、心肌炎症和左心室功能障碍相关，通过常规和 2D 斑点追踪超声心动图评估。在 IGC 期间进行的 p66 体内基因沉默抑制了 ROS 的产生并恢复了心脏功能。此外，我们表明，甲基转移酶 DNMT3b 和去乙酰化酶 SIRT1 的失调导致 p66 启动子上的 CpG 去甲基化和组蛋白 3 乙酰化，从而导致该适应蛋白的持续转录。糖尿病心脏中改变的 DNMT3b/SIRT1 轴可以通过 miR-218 和 miR-34a 的上调来解释。事实上，在高糖暴露的人心肌细胞中，抑制这些 miRNA 可恢复 DNMT3b 和 SIRT1 的表达，并消除 p66 启动子上的不利表观遗传特征。一致地，重新编程 miR-218 和 miR-34a 可减轻持续的 p66 表达和 ROS 产生。
在糖尿病左心室功能障碍中，一种复杂的表观遗传机制将 miRNA 和染色质修饰酶联系起来，驱动持续的 p66 转录和 ROS 生成。我们的结果为药物靶向表观遗传网络以减轻糖尿病心肌病的临床负担奠定了基础。
