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

Research output: Contribution to journalArticle

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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

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Carbon Monoxide
Down-Regulation
Endothelial cells
Endothelial Cells
3' Untranslated Regions
Messenger RNA
Heme Oxygenase-1
Networks (circuits)
Acetylcysteine
Heme
Vascular Diseases
Bilirubin
Small Interfering RNA
Oxidation-Reduction
Blood Vessels
Iron
Recovery
Degradation
tricarbonyldichlororuthenium (II) dimer

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Choi, Seunghwan ; Kim, Joohwan ; Kim, Ji Hee ; Lee, Dong Keon ; Park, Wonjin ; Park, Minsik ; Kim, Suji ; Hwang, Jong Yun ; Won, Moo Ho ; Choi, Yoon Kyung ; Ryoo, Sungwoo ; Ha, Kwon Soo ; Kwon, Young-Guen ; Kim, Young Myeong. / Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis. In: Experimental and Molecular Medicine. 2017 ; Vol. 49, No. 11.
@article{83cf68868f3742879e04185e0acc6b37,
title = "Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis",
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.",
author = "Seunghwan Choi and Joohwan Kim and Kim, {Ji Hee} and Lee, {Dong Keon} and Wonjin Park and Minsik Park and Suji Kim and Hwang, {Jong Yun} and Won, {Moo Ho} and Choi, {Yoon Kyung} and Sungwoo Ryoo and Ha, {Kwon Soo} and Young-Guen Kwon and Kim, {Young Myeong}",
year = "2017",
month = "11",
day = "3",
doi = "10.1038/emm.2017.193",
language = "English",
volume = "49",
journal = "Experimental and Molecular Medicine",
issn = "1226-3613",
publisher = "Korean Society of Med. Biochemistry and Mol. Biology",
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Choi, S, Kim, J, Kim, JH, Lee, DK, Park, W, Park, M, Kim, S, Hwang, JY, Won, MH, Choi, YK, Ryoo, S, Ha, KS, Kwon, Y-G & Kim, YM 2017, 'Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis', Experimental and Molecular Medicine, vol. 49, no. 11, e403. https://doi.org/10.1038/emm.2017.193

Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis. / Choi, Seunghwan; Kim, Joohwan; Kim, Ji Hee; Lee, Dong Keon; Park, Wonjin; Park, Minsik; Kim, Suji; Hwang, Jong Yun; Won, Moo Ho; Choi, Yoon Kyung; Ryoo, Sungwoo; Ha, Kwon Soo; Kwon, Young-Guen; Kim, Young Myeong.

In: Experimental and Molecular Medicine, Vol. 49, No. 11, e403, 03.11.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis

AU - Choi, Seunghwan

AU - Kim, Joohwan

AU - Kim, Ji Hee

AU - Lee, Dong Keon

AU - Park, Wonjin

AU - Park, Minsik

AU - Kim, Suji

AU - Hwang, Jong Yun

AU - Won, Moo Ho

AU - Choi, Yoon Kyung

AU - Ryoo, Sungwoo

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2017/11/3

Y1 - 2017/11/3

N2 - 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.

AB - 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.

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DO - 10.1038/emm.2017.193

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