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Redox regulation of cardiomyocyte cell cycling via an ERK1/2 and c-Myc-dependent activation of cyclin D2 transcription
- Source :
- Journal of Molecular and Cellular Cardiology
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Adult mammalian cardiomyocytes have a very limited capacity to proliferate, and consequently the loss of cells after cardiac stress promotes heart failure. Recent evidence suggests that administration of hydrogen peroxide (H2O2), can regulate redox-dependent signalling pathway(s) to promote cardiomyocyte proliferation in vitro, but the potential relevance of such a pathway in vivo has not been tested. We have generated a transgenic (Tg) mouse model in which the H2O2-generating enzyme, NADPH oxidase 4 (Nox4), is overexpressed within the postnatal cardiomyocytes, and observed that the hearts of 1–3 week old Tg mice pups are larger in comparison to wild type (Wt) littermate controls. We demonstrate that the cardiomyocytes of Tg mouse pups have increased cell cycling capacity in vivo as determined by incorporation of 5-bromo-2′-deoxyuridine. Further, microarray analyses of the transcriptome of these Tg mouse hearts suggested that the expression of cyclin D2 is significantly increased. We investigated the molecular mechanisms which underlie this more proliferative phenotype in isolated neonatal rat cardiomyocytes (NRCs) in vitro, and demonstrate that Nox4 overexpression mediates an H2O2-dependent activation of the ERK1/2 signalling pathway, which in turn phosphorylates and activates the transcription factor c-myc. This results in a significant increase in cyclin D2 expression, which we show to be mediated, at least in part, by cis-acting c-myc binding sites within the proximal cyclin D2 promoter. Overexpression of Nox4 in NRCs results in an increase in their proliferative capacity that is ablated by the silencing of cyclin D2. We further demonstrate activation of the ERK1/2 signalling pathway, increased phosphorylation of c-myc and significantly increased expression of cyclin D2 protein in the Nox4 Tg hearts. We suggest that this pathway acts to maintain the proliferative capacity of cardiomyocytes in Nox4 Tg pups in vivo and so delays their exit from the cell cycle after birth.<br />Highlights • Cardiomyocyte cell cycling is under redox control in vivo. • Nox4 is a potential source of ROS regulating this process. • Redox activation of ERK1/2 promotes cyclin D2 transcription via c-myc activation. • Promotion of proliferation via increased cyclin D2 may be useful therapeutically.
- Subjects :
- Redox signalling
Transcription, Genetic
Molecular Sequence Data
Cardiomegaly
Mice, Transgenic
Biology
AdβGal, adenoviral β-galactosidase
BrdU, bromodeoxyuridine
Proto-Oncogene Proteins c-myc
Nox4
Cyclin D2
Downregulation and upregulation
Tg, transgenic
NRC, neonatal rat cardiomyocyte
Animals
Myocytes, Cardiac
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Promoter Regions, Genetic
Transcription factor
Molecular Biology
Conserved Sequence
AdNox4, adenoviral Nox4
PEG, polyethylene glycol
Cell Proliferation
Binding Sites
Base Sequence
ERK1/2
Cell growth
Myocardium
Cell Cycle
Wild type
NOX4
NADPH Oxidases
Cell cycle
Molecular biology
Hedgehog signaling pathway
Rats
Up-Regulation
c-Myc
Animals, Newborn
NADPH Oxidase 4
Cardiomyocyte proliferation
Original Article
Reactive Oxygen Species
Cardiology and Cardiovascular Medicine
Wt, wild type
Oxidation-Reduction
Subjects
Details
- ISSN :
- 00222828
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular and Cellular Cardiology
- Accession number :
- edsair.doi.dedup.....65f79e94568758a813943a48138269cd
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2014.10.017