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Reactive oxygen species (ROS) levels rise during ischaemia and reperfusion and may contribute to myocardial injury, remodelling and progression to heart failure. ROS (hydrogen peroxide; H2O2) activates both apoptotic and pro-survival signalling pathways, although at higher concentrations cardiomyocyte death invariably results. Here, transcriptional responses of cardiomyocytes to varying concentrations and duration of H2O2 were investigated.
Neonatal rat ventricular myocytes were exposed to 0.05–1.0 mM H2O2 for up to 6 h. Messenger RNA expression of selected genes was analysed by quantitative PCR. Cycloheximide was used to define immediate early genes (IEG) and second-phase genes.
Transcription factors of activating protein 1 (AP-1) and early growth response (EGR) families were upregulated rapidly and transiently by 0.1–1 mM H2O2, concentrations, which induce cardiomyocyte apoptosis and are IEG. In contrast, upregulation of transcripts for antioxidant proteins (second-phase genes) was slower and more sustained, occurring at a lower concentration of H2O2 (0.05–0.5 mM).
AP-1, EGR and antioxidant transcripts were regulated by H2O2 in a time and concentration-dependent manner. Induction of antioxidant expression at lower concentrations of H2O2 could represent enhancement of ROS-scavenging capacity to prevent apoptosis. At higher H2O2 concentrations, the AP-1 and EGR transcription factor IEG may mediate apoptosis. These studies increase the understanding of transcriptional responses in cardiomyocytes to ROS.
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