NF-κB Transcriptional Activity Indispensably Mediates Hypoxia–Reoxygenation Stress-Induced microRNA-210 Expression
Peer reviewed, Journal article
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Original versionInternational Journal of Molecular Sciences. 2023, 24(7), 6618. 10.3390/ijms24076618
Ischemia–reperfusion (I-R) injury is a cardinal pathophysiological hallmark of ischemic heart disease (IHD). Despite significant advances in the understanding of what causes I-R injury and hypoxia–reoxygenation (H-R) stress, viable molecular strategies that could be targeted for the treatment of the deleterious biochemical pathways activated during I-R remain elusive. The master hypoxamiR, microRNA-210 (miR-210), is a major determinant of protective cellular adaptation to hypoxia stress but exacerbates apoptotic cell death during cellular reoxygenation. While the hypoxia-induced transcriptional up-regulation of miR-210 is well delineated, the cellular mechanisms and molecular entities that regulate the transcriptional induction of miR-210 during the cellular reoxygenation phase have not been elucidated yet. Herein, in immortalized AC-16 cardiomyocytes, we delineated the indispensable role of the ubiquitously expressed transcription factor, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in H-R-induced miR-210 expression during cellular reoxygenation. Using dominant negative and dominant active expression vectors encoding kinases to competitively inhibit NF-κB activation, we elucidated NF-κB activation as a significant mediator of H-R-induced miR-210 expression. Ensuing molecular assays revealed a direct NF-κB-mediated transcriptional up-regulation of miR-210 expression in response to the H-R challenge that is characterized by the NF-κB-mediated reorchestration of the entire repertoire of histone modification changes that are a signatory of a permissive actively transcribed miR-210 promoter. Our study confers a novel insight identifying NF-κB as a potential novel molecular target to combat H-R-elicited miR-210 expression that fosters augmented cardiomyocyte cell death.