Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD
Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD
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DOI：
10.1161/circresaha.120.317132
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发表时间：
2020-10-23
影响因子：
20.1
通讯作者：
Cosentino, Francesco
中科院分区：
文献类型：
--
作者：
Hussain, Shafaat;Khan, Abdul Waheed;Cosentino, Francesco
原理：高血压诱导的活性氧是心功能不全的关键介质. JunD（Jund proto-oncogene subunit）是AP-1（activator protein-1）转录因子家族的一员，是抗氧化应激的主要看门人。然而，其贡献的氧化还原状态和炎症在糖尿病心脏仍有待阐明。目的：本研究探讨的作用，JunD在高血糖诱导和活性氧驱动的心肌dysfunctions.Methods和结果：JunD的mRNA和蛋白质表达减少，与链脲佐菌素诱导的糖尿病小鼠的心肌相比，控制。通过电子自旋共振波谱以及常规和二维斑点追踪超声心动图评估，JunD下调与氧化应激和左心室功能障碍相关。此外，心肌自由基清除剂超氧化物歧化酶1和醛脱氢酶2的表达减少，而NOX 2（NADPH [烟酰胺腺嘌呤二核苷酸磷酸酶]氧化酶亚基2）和NOX 4（NADPH [烟酰胺腺嘌呤二核苷酸磷酸酶]氧化酶亚基4）上调。氧化还原变化与NF-κ B（核因子κ B）结合活性和炎症介质表达增加相关。有趣的是，通过α-MHC（α-肌球蛋白重链）启动子（α-MHC JunD（tg））具有心脏特异性JunD过表达的小鼠被保护免于高血糖诱导的心脏功能障碍。我们还发现，JunD的表观遗传调控启动子超甲基化，组蛋白标记的翻译后修饰，和翻译抑制的miRNA（microRNA）-673/menin。降低JunD mRNA和蛋白表达证实左心室标本中获得的2型糖尿病患者相比，nondiabetic subjects.Conclusions：在这里，我们表明，一个复杂的表观遗传机制，涉及DNA甲基化，组蛋白修饰，和microRNA介导高血糖诱导的JunD下调和心肌功能障碍的实验和人类糖尿病。我们的研究结果为JunD的组织特异性治疗调制铺平了道路，以预防糖尿病心肌病。
Rationale:Hyperglycemia -induced reactive oxygen species are key mediators of cardiac dysfunction. JunD (Jund proto-oncogene subunit), a member of the AP-1 (activator protein-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to redox state and inflammation in the diabetic heart remains to be elucidated.Objective:The present study investigates the role of JunD in hyperglycemia-induced and reactive oxygen species-driven myocardial dysfunction.Methods and Results:JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes mellitus as compared to controls. JunD downregulation was associated with oxidative stress and left ventricular dysfunction assessed by electron spin resonance spectroscopy as well as conventional and 2-dimensional speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the NOX2 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 2) and NOX4 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 4) were upregulated. The redox changes were associated with increased NF-kappa B (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the alpha MHC (alpha- myosin heavy chain) promoter (alpha MHC JunD(tg)) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, post-translational modification of histone marks, and translational repression by miRNA (microRNA)-673/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes mellitus as compared to nondiabetic subjects.Conclusions:Here, we show that a complex epigenetic machinery involving DNA methylation, histone modifications, and microRNAs mediates hyperglycemia-induced JunD downregulation and myocardial dysfunction in experimental and human diabetes mellitus. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.