Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis.
- Author:
Seunghwan CHOI
1
;
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
Author Information
- Publication Type:Original Article
- MeSH: Acetylcysteine; Bilirubin; Carbon Monoxide*; Carbon*; Down-Regulation*; Endothelial Cells; Heme; Humans; Iron; RNA, Messenger; RNA, Small Interfering; Vascular Diseases
- From:Experimental & Molecular Medicine 2017;49(11):e403-
- CountryRepublic of Korea
- Language:English
- 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.
