Exp Mol Med.
2017 Nov;49(11):e403. 10.1038/emm.2017.193.
Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis
- Affiliations
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- 1Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, South Korea. ymkim@kangwon.ac.kr
- 2Departments of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, South Korea.
- 3Department of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do, South Korea.
- 4Department of Integrative Bioscience and Biotechnology, Konkuk University, Seoul, South Korea.
- 5Department of Biology, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, South Korea.
- 6Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
- KMID: 2396808
- DOI: http://doi.org/10.1038/emm.2017.193
Abstract
- Heme oxygenase-1-derived carbon monoxide prevents inflammatory vascular disorders. To date, there is no clear evidence that HO-1/CO prevents endothelial dysfunction associated with the downregulation of endothelial NO synthesis in human endothelial cells stimulated with TNF-α. Here, we found that the CO-releasing compound CORM-2 prevented TNF-α-mediated decreases in eNOS expression and NO/cGMP production, without affecting eNOS promoter activity, by maintaining the functional activity of the eNOS mRNA 3"²-untranslated region. By contrast, CORM-2 inhibited MIR155HG expression and miR-155-5p biogenesis in TNF-α-stimulated endothelial cells, resulting in recovery of the 3"²-UTR activity of eNOS mRNA, a target of miR-155-5p. The beneficial effect of CORM-2 was blocked by an NF-κB inhibitor, a miR-155-5p mimic, a HO-1 inhibitor and siRNA against HO-1, indicating that CO rescues TNF-α-induced eNOS downregulation through NF-κB-responsive miR-155-5p expression via HO-1 induction; similar protective effects of ectopic HO-1 expression and bilirubin were observed in endothelial cells treated with TNF-α. Moreover, heme degradation products, except iron and N-acetylcysteine prevented Hâ‚‚Oâ‚‚-mediated miR-155-5p biogenesis and eNOS downregulation. These data demonstrate that CO prevents TNF-α-mediated eNOS downregulation by inhibiting redox-sensitive miR-155-5p biogenesis through a positive forward circuit between CO and HO-1 induction. This circuit may play an important preventive role in inflammatory endothelial dysfunction associated with human vascular diseases.
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