Inflammatory cytokines, including tumor necrosis factor- (TNF), were elevated in patients with cardiovascular diseases and are also considered as crucial factors in the pathogenesis of preeclampsia; however, the underlying pathogenic mechanism has not been clearly elucidated. This study provides novel evidence that TNF leads to endothelial dysfunction associated with hypertension and vascular remodeling in preeclampsia through down-regulation of endothelial nitric-oxide synthase (eNOS) by NF-B– dependent biogenesis of microRNA (miR)-31-5p, which targets eNOS mRNA. In this study, we found that miR-31-5p was up-regulated in sera from patients with preeclampsia and in human endothelial cells treated with TNF. TNF-mediated induction of miR-31-5p was blocked by an NF-B inhibitor and NF-B p65 knockdown but not by mito-gen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase inhibitors, indicating that NF-B is essential for biogenesis of miR-31-5p. The treatment of human endothelial cells with TNF or miR-31-5p mimics decreased endothelial nitric-oxide synthase (eNOS) mRNA stability without affecting eNOS promoter activity, resulting in inhibition of eNOS expression and NO/cGMP production through blocking of the functional activity of the eNOS mRNA 3-UTR. Moreover, TNF and miR-31-5p mimic evoked endothelial dysfunction associated with defects in angiogenesis, trophoblastic invasion, and vasorelaxation in an ex vivo cultured model of human placental arterial vessels, which are typical features of preeclampsia. These results suggest that NF-B–responsive miR-31-5p elicits endothelial dysfunction, hypertension, and vascular remodeling via post-transcriptional down-regulation of eNOS and is a molecular risk factor in the pathogenesis and development of preeclampsia.
Bibliographical noteFunding Information:
This work was supported by National Research Foundation of Korea (NRF) Grant 2016M3A9B6903103 funded by the Korea Government (MSIP). The authors declare that they have no conflicts of interest with the contents of this article.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology