Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD

Abstract

Rationale: Hyperglycemia­induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. JunD, a member of the Activated Protein­1 (AP-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 ROS-driven myocardial dysfunction. Methods and Results: JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes 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 2D speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits NOX2 and NOX4 were upregulated. The redox changes were associated with increased NF-kappaB binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the α­myosin heavy chain promoter (α­MHC­ JunD tg ) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, posttranslational modification of histone marks and translational repression by miRNA-673/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes and heart failure as compared to non-diabetic 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. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.

JunD Regulates Pancreatic β-Cells Function by Altering Lipid Accumulation

“…The AP-1 transcription factor JunD regulates various target genes involved in cell growth, proliferation, and apoptosis (9,39). Recently, JunD has emerged as a vital player in the setting of metabolic diseases (11)(12)(13)(14)40). Hyperglycemia promotes ROS production by downregulating JunD expression, which leads to cardiac dysfunction.…”

Oxidative Stress-Induced Ferroptosis in Cardiovascular Diseases and Epigenetic Mechanisms

“…Upregulation of miR-218 and miR-34a results in changes of the DNMT3b/SIRT1 axis in the diabetic heart, which may be a potential target to cure diabetic cardiomyopathy ( Costantino et al, 2018 ). Another study, conducted by Hussain et al (2020) , found that JunD (a member of AP-1 transcript family) mRNA and protein are shown to have decreased expression in STZ-induced diabetes, which is relevant to oxidative stress, and is regulated by DNA hypermethylation, post-translational modification of histone markers, and translational inhibition by miRNA. Xu et al treated diabetic mice with HDAC3 inhibitor, RGFP966, and found improved heart dysfunction, hypertrophy, fibrosis, and diminished oxidative stress.…”

Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Glucose Homeostasis and Diabetes-Related Endothelial Cell Dysfunction

“…A wide variety of protein signalling cascades, hormones and cytokines including mitogen activated protein kinase (MAPK), interferon gamma (IFNγ), tumour necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), and angiotensin II act to increase Nox through transcription factors [ 44 , 45 , 46 , 47 ]. Nox expression is negatively regulated by JunD [ 48 ]. Initial work identified peroxisome proliferator-activated receptor gamma (PPAR-γ) as a negative regulator of Nox, [ 49 ] however recent work has suggested Nox-dependent generation of O 2 •− is dependent on other types of PPAR (PPARα and PPARβ/δ) [ 50 ].…”

“…This may be in part due to hyperacetylation at Nox promotor regions, blocking the action of RNA polymerase II and c-jun (a key constituent protein unit found in AP-1) when HDAC is inhibited [ 64 , 66 , 67 ]. DNA methylation and histone modification may play a key role in the regulation of Nox [ 48 ]. DNA at the Rac1 promoter region (a key subunit of Nox1/2) undergoes methylation in response to hyperglycaemia within retinal ECs and is associated with increased Nox expression and activity [ 68 ].…”

“…DNA at the Rac1 promoter region (a key subunit of Nox1/2) undergoes methylation in response to hyperglycaemia within retinal ECs and is associated with increased Nox expression and activity [ 68 ]. Furthermore, Hussain et al elegantly showed within a diabetic murine model that the downregulation of JunD (a negative regulator of Nox) was mediated by hypermethylation and post-translational histone methylation within the promoter region of JunD [ 48 ]. Similarly, increased histone acetylation (HAT) within the promoter region of Nox5 (with an associated increased Nox5 activity) has been found in human atherosclerotic tissue samples [ 69 ].…”