Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis

Seunghwan Choi, Joohwan Kim, Ji Hee Kim, Dong Keon Lee, Wonjin Park, Minsik Park, Suji Kim, Jong Yun Hwang, Moo Ho Won, Yoon Kyung Choi, Sungwoo Ryoo, Kwon Soo Ha, Young Guen Kwon, Young Myeong Kim

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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′-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′-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 H2O2-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.

Original languageEnglish
Article numbere403
JournalExperimental and Molecular Medicine
Volume49
Issue number11
DOIs
Publication statusPublished - 2017 Nov 3

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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    Choi, S., Kim, J., Kim, J. H., Lee, D. K., Park, W., Park, M., Kim, S., Hwang, J. Y., Won, M. H., Choi, Y. K., Ryoo, S., Ha, K. S., Kwon, Y. G., & Kim, Y. M. (2017). Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis. Experimental and Molecular Medicine, 49(11), [e403]. https://doi.org/10.1038/emm.2017.193