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.
Highlights
Nitric oxide (NO) produced from L-arginine by endothelial nitric oxide synthase exerts multiple beneficial functions, such as vasorelaxation, anti-inflammation and antiapoptosis, in the vasculature and plays a critical role in vascular homeostasis and disorders.[1]
The tumor necrosis factor (TNF)-α-mediated decrease in NO production was effectively recovered by CORM-2 treatment, and this recovery effect was abrogated by the endothelial nitric oxide synthase (eNOS) inhibitor L-NIO (Figure 1e and f), indicating that carbon monoxide (CO) rescues NO production in an eNOS-dependent manner
These results suggest that CO prevents the TNF-α-induced decrease in eNOS expression and NO production
Summary
Nitric oxide (NO) produced from L-arginine by endothelial nitric oxide synthase (eNOS) exerts multiple beneficial functions, such as vasorelaxation, anti-inflammation and antiapoptosis, in the vasculature and plays a critical role in vascular homeostasis and disorders.[1]. A great deal of evidence shows that the eNOS/NO pathway can be regulated in response to a wide variety of pathophysiological stimuli.[4,5,6,7,8,9,10] The activity of eNOS is mostly regulated by multiple post-translational processes, such as Ca2+-dependent dimerization, phosphorylation, subcellular localization and protein–protein interactions.[4,5] eNOS is known as a constitutive enzyme, its expression can be modulated at both transcriptional and post-transcriptional levels by various pathophysiological stresses and stimuli.[6,7,8,9,10].
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