NF-κB–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via down-regulation of endothelial nitric-oxide synthase

Abstract

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-Bdependent 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 mitogen-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 nitricoxide 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 posttranscriptional down-regulation of eNOS and is a molecular risk factor in the pathogenesis and development of preeclampsia.

The NF‐κB‐modulated miR‐19a‐3p enhances malignancy of human ovarian cancer cells through inhibition of IGFBP‐3 expression

“…Aberrant miRNAs expression can also be regulated by NF‐κB. The expression of miR‐31‐5p, miR‐146a, and miR‐548as‐3p can be upregulated by NF‐κB, whereas miR‐195 and miR‐497 are negatively regulated with NF‐κB . It has been reported that miR‐19a promotes colitis‐associated colorectal cancer by regulating tumor necrosis factor α‐induced protein 3‐NF‐κB feedback loops and microRNA‐19a promotes cell viability and migration of chondrocytes via upregulation of SOX9 through the NF‐κB pathway .…”

Long noncoding RNA LINC00511 regulates the proliferation, apoptosis, invasion and autophagy of trophoblast cells to mediate pre‐eclampsia progression through modulating the miR‐31‐5p/homeobox protein A7 axis

“…Kim et al reported that miR-31-5p was highly expressed in PE, and its overexpression could inhibit the proliferation and invasion of endothelial cells. 27 Our recovery experiment results indicated that miR-31-5p could be competitively bound by LINC00511 and indirectly regulated HOXA7 expression, thereby achieving the regulation of the biological function of trophoblast cells.…”

Fate decision of satellite cell differentiation and self-renewal by miR-31-IL34 axis

“…The results suggest that the reduction of cycling SCs is attributed to asymmetric cell fate segregation, which generates one differentiated cell and one quiescent stem cell. Upregulation of miR-31 has been shown to decrease the activity of both endothelial and neuronal nitric oxide synthase (NOS), which participate in muscle repair by modulating SC functions [39][40][41]. Inhibition of nitric oxide signaling in miR-31-KO cultures by treatment with an NOS inhibitor, L- Analysis of the molecular mechanisms revealed that miR-31 promotes the expansion of proliferating SCs by repressing IL34, a cytokine produced by a wide range of cells.…”