Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD.
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-κB (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the α MHC (α- myosin heavy chain) promoter (α MHC JunD) 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.
['Hussain|Shafaat|S|', 'Khan|Abdul Waheed|AW|', 'Akhmedov|Alexander|A|', 'Suades|Rosa|R|', 'Costantino|Sarah|S|', 'Paneni|Francesco|F|', 'Caidahl|Kenneth|K|', 'Mohammed|Shafeeq A|SA|', 'Hage|Camilla|C|', 'Gkolfos|Christos|C|', 'Björck|Hanna|H|', 'Pernow|John|J|', 'Lund|Lars H|LH|', 'Lüscher|Thomas F|TF|', 'Cosentino|Francesco|F|']
D000818:Animals D019175:DNA Methylation D058065:Diabetic Cardiomyopathies D044127:Epigenesis, Genetic D042421:Histone Code D006801:Humans D006943:Hyperglycemia D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D035683:MicroRNAs D009206:Myocardium D000074662:NADPH Oxidase 2 D000074663:NADPH Oxidase 4 D016328:NF-kappa B D000090063:Proto-Oncogene Mas D011518:Proto-Oncogene Proteins D016755:Proto-Oncogene Proteins c-jun D017382:Reactive Oxygen Species D000072105:Superoxide Dismutase-1
reactive oxygen species transcription factors diabetes mellitus microRNA heart failure