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KMID : 0620920170490110016
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Experimental & Molecular Medicine
2017 Volume.49 No. 11 p.16 ~ p.16
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Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis
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Choi Seung-Hwan
Kim Joo-Hwan
Kim Ji-Hee
Lee Dong-Keon
Park Won-Jin
Park Min-Sik
Kim Su-Ji
Hwang Jong-Yun
Won Moo-Ho
Choi Yoon-Kyung
Ryoo Sung-Woo
Ha Kwon-Soo
Kwon Young-Guen
Kim Young-Myeong
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Abstract
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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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KEYWORD
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Mechanisms of disease, miRNAs, Tumour-necrosis factors
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