NF-B–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via downregulation of endothelial nitric-oxide synthase

Suji Kim, Kyu Sun Lee, Seunghwan Choi, Joohwan Kim, Dong Keon Lee, Minsik Park, Wonjin Park, Tae Hoon Kim, Jong Yun Hwang, Moo Ho Won, Hansoo Lee, Sungwoo Ryoo, Kwon Soo Ha, Young-Guen Kwon, Young Myeong Kim

Research output: Contribution to journalArticle

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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-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.

Original languageEnglish
Pages (from-to)18989-19000
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number49
DOIs
Publication statusPublished - 2018 Jan 1

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Nitric Oxide Synthase Type III
Pre-Eclampsia
MicroRNAs
Down-Regulation
Tumor Necrosis Factor-alpha
Endothelial cells
Messenger RNA
Endothelial Cells
Phosphatidylinositol 3-Kinase
Hypertension
RNA Stability
3' Untranslated Regions
Vasodilation
Protein Kinases
Cardiovascular Diseases
Cytokines
Defects
Serum

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kim, Suji ; Lee, Kyu Sun ; Choi, Seunghwan ; Kim, Joohwan ; Lee, Dong Keon ; Park, Minsik ; Park, Wonjin ; Kim, Tae Hoon ; Hwang, Jong Yun ; Won, Moo Ho ; Lee, Hansoo ; Ryoo, Sungwoo ; Ha, Kwon Soo ; Kwon, Young-Guen ; Kim, Young Myeong. / NF-B–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via downregulation of endothelial nitric-oxide synthase. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 49. pp. 18989-19000.
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title = "NF-B–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via downregulation 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-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.",
author = "Suji Kim and Lee, {Kyu Sun} and Seunghwan Choi and Joohwan Kim and Lee, {Dong Keon} and Minsik Park and Wonjin Park and Kim, {Tae Hoon} and Hwang, {Jong Yun} and Won, {Moo Ho} and Hansoo Lee and Sungwoo Ryoo and Ha, {Kwon Soo} and Young-Guen Kwon and Kim, {Young Myeong}",
year = "2018",
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Kim, S, Lee, KS, Choi, S, Kim, J, Lee, DK, Park, M, Park, W, Kim, TH, Hwang, JY, Won, MH, Lee, H, Ryoo, S, Ha, KS, Kwon, Y-G & Kim, YM 2018, 'NF-B–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via downregulation of endothelial nitric-oxide synthase', Journal of Biological Chemistry, vol. 293, no. 49, pp. 18989-19000. https://doi.org/10.1074/jbc.RA118.005197

NF-B–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via downregulation of endothelial nitric-oxide synthase. / Kim, Suji; Lee, Kyu Sun; Choi, Seunghwan; Kim, Joohwan; Lee, Dong Keon; Park, Minsik; Park, Wonjin; Kim, Tae Hoon; Hwang, Jong Yun; Won, Moo Ho; Lee, Hansoo; Ryoo, Sungwoo; Ha, Kwon Soo; Kwon, Young-Guen; Kim, Young Myeong.

In: Journal of Biological Chemistry, Vol. 293, No. 49, 01.01.2018, p. 18989-19000.

Research output: Contribution to journalArticle

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T1 - NF-B–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via downregulation of endothelial nitric-oxide synthase

AU - Kim, Suji

AU - Lee, Kyu Sun

AU - Choi, Seunghwan

AU - Kim, Joohwan

AU - Lee, Dong Keon

AU - Park, Minsik

AU - Park, Wonjin

AU - Kim, Tae Hoon

AU - Hwang, Jong Yun

AU - Won, Moo Ho

AU - Lee, Hansoo

AU - Ryoo, Sungwoo

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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