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Hyperglycemia Induc...
Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD
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Hussain, S. (författare)
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Khan, A. W. (författare)
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Akhmedov, A. (författare)
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Suades, R. (författare)
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Costantino, S. (författare)
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Paneni, F. (författare)
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- Caidahl, Kenneth, 1949 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Mohammed, S. A. (författare)
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Hage, C. (författare)
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Gkolfos, C. (författare)
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Bjorck, H. (författare)
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Pernow, J. (författare)
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Lund, L. H. (författare)
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Luscher, T. F. (författare)
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Cosentino, F. (författare)
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(creator_code:org_t)
- Ovid Technologies (Wolters Kluwer Health), 2020
- 2020
- Engelska.
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Ingår i: Circulation Research. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7330 .- 1524-4571. ; 127:10, s. 1261-1273
- Relaterad länk:
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https://www.ahajourn...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- diabetes mellitus
- heart failure
- microRNA
- reactive oxygen species
- transcription factors
- histone methyltransferase complex
- oxidative stress
- diabetic
- cardiomyopathy
- gene-expression
- menin
- ap-1
- activation
- angiogenesis
- transcription
- hypertrophy
- Cardiovascular System & Cardiology
- Hematology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Hussain, S.
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Khan, A. W.
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Akhmedov, A.
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Suades, R.
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Costantino, S.
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Paneni, F.
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visa fler...
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Caidahl, Kenneth ...
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Mohammed, S. A.
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Hage, C.
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Gkolfos, C.
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Bjorck, H.
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Pernow, J.
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Lund, L. H.
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Luscher, T. F.
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Cosentino, F.
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Kardiologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
- Artiklar i publikationen
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Circulation Rese ...
- Av lärosätet
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Göteborgs universitet