The NADPH oxidase NOX4 drives cardiac differentiation: Role in regulating cardiac transcription factors and MAP kinase activation.
Reactive oxygen species (ROS) generated by the NOX family of NADPH oxidases have been described to act as second messengers regulating cell growth and differentiation. However, such a function has hitherto not been convincingly demonstrated. We investigated the role of NOX-derived ROS in cardiac differentiation using mouse embryonic stem cells. ROS scavengers prevented the appearance of spontaneously beating cardiac cells within embryoid bodies. Down-regulation of NOX4, the major NOX isoform present during early stages of differentiation, suppressed cardiogenesis. This was rescued by a pulse of low concentrations of hydrogen peroxide 4 d before spontaneous beating appears. Mechanisms of ROS-dependent signaling included p38 mitogen-activated protein kinase (MAPK) activation and nuclear translocation of the cardiac transcription factor myocyte enhancer factor 2C (MEF2C). Our results provide first molecular evidence that the NOX family of NADPH oxidases regulate vertebrate developmental processes.
Li
Jian
J
Laboratory of Biology of Aging, Department of Rehabilitation and Geriatrics, Geneva University Hospitals, 1225 Chêne-Bourg, Switzerland.
Stouffs
Michael
M
Serrander
Lena
L
Banfi
Botond
B
Bettiol
Esther
E
Charnay
Yves
Y
Steger
Klaus
K
Krause
Karl-Heinz
KH
Jaconi
Marisa E
ME
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016166:Free Radical Scavengers; D007527:Isoenzymes; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases