Aspirin prevents TNF-α-induced endothelial cell dysfunction by regulating the NF-κB-dependent miR-155/eNOS pathway: Role of a miR-155/eNOS axis in preeclampsia

Joohwan Kim, Kyu Sun Lee, Ji Hee Kim, Dong Keon Lee, Minsik Park, Seunghwan Choi, Wonjin Park, Suji Kim, Yoon Kyoung Choi, Jong Yun Hwang, Jongseon Choe, Moo Ho Won, Dooil Jeoung, Hansoo Lee, Sungwoo Ryoo, Kwon Soo Ha, Young-Guen Kwon, Young Myeong Kim

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Abstract

Preeclampsia is an inflammatory disease with endothelial cell dysfunction that occurs via decreased endothelial nitric oxide synthase/nitric oxide (eNOS/NO) activity. Aspirin reduces the incidence of hypertensive pregnancy complications. However, the underlying mechanism has not been clearly explained. Here, we found that tumor necrosis factor (TNF)-α, microRNA (miR)−155, and eNOS levels as well as endothelial redox phenotype were differentially regulated in preeclamptic patients, implying the involvement of TNF-α- and redox signal-mediated miR-155 biogenesis and eNOS downregulation in the pathogenesis of preeclampsia. Aspirin prevented the TNF-α-mediated increase in miR-155 biogenesis and decreases in eNOS expression and NO/cGMP production in cultured human umbilical vein endothelial cells (HUVECs). Similar effects of aspirin were also observed in HUVECs treated with H 2 O 2 . The preventive effects of aspirin was associated with the inhibition of nuclear factor-κB (NF-κB)-dependent MIR155HG (miR-155 host gene) expression. Aspirin recovered the TNF-α-mediated decrease in wild-type, but not mutant, eNOS 3′-untranslated region reporter activity, whose effect was blocked by miR-155 mimic. Moreover, aspirin prevented TNF-α-mediated endothelial cell dysfunction associated with impaired vasorelaxation, angiogenesis, and trophoblast invasion, and the preventive effects were blocked by miR-155 mimic or an eNOS inhibitor. Aspirin rescued TNF-α-mediated eNOS downregulation coupled with endothelial dysfunction by inhibiting NF-κB-dependent transcriptional miR-155 biogenesis. Thus, the redox-sensitive NF-κB/miR-155/eNOS axis may be crucial in the pathogenesis of vascular disorders including preeclampsia.

Original languageEnglish
Pages (from-to)185-198
Number of pages14
JournalFree Radical Biology and Medicine
Volume104
DOIs
Publication statusPublished - 2017 Mar 1

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Endothelial cells
Pre-Eclampsia
MicroRNAs
Aspirin
Endothelial Cells
Tumor Necrosis Factor-alpha
Oxidation-Reduction
Human Umbilical Vein Endothelial Cells
Down-Regulation
Pregnancy Complications
Nitric Oxide Synthase Type III
Trophoblasts
3' Untranslated Regions
Gene expression
Vasodilation
Blood Vessels
Nitric Oxide
Phenotype
Gene Expression
Incidence

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

Kim, Joohwan ; Lee, Kyu Sun ; Kim, Ji Hee ; Lee, Dong Keon ; Park, Minsik ; Choi, Seunghwan ; Park, Wonjin ; Kim, Suji ; Choi, Yoon Kyoung ; Hwang, Jong Yun ; Choe, Jongseon ; Won, Moo Ho ; Jeoung, Dooil ; Lee, Hansoo ; Ryoo, Sungwoo ; Ha, Kwon Soo ; Kwon, Young-Guen ; Kim, Young Myeong. / Aspirin prevents TNF-α-induced endothelial cell dysfunction by regulating the NF-κB-dependent miR-155/eNOS pathway : Role of a miR-155/eNOS axis in preeclampsia. In: Free Radical Biology and Medicine. 2017 ; Vol. 104. pp. 185-198.
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title = "Aspirin prevents TNF-α-induced endothelial cell dysfunction by regulating the NF-κB-dependent miR-155/eNOS pathway: Role of a miR-155/eNOS axis in preeclampsia",
abstract = "Preeclampsia is an inflammatory disease with endothelial cell dysfunction that occurs via decreased endothelial nitric oxide synthase/nitric oxide (eNOS/NO) activity. Aspirin reduces the incidence of hypertensive pregnancy complications. However, the underlying mechanism has not been clearly explained. Here, we found that tumor necrosis factor (TNF)-α, microRNA (miR)−155, and eNOS levels as well as endothelial redox phenotype were differentially regulated in preeclamptic patients, implying the involvement of TNF-α- and redox signal-mediated miR-155 biogenesis and eNOS downregulation in the pathogenesis of preeclampsia. Aspirin prevented the TNF-α-mediated increase in miR-155 biogenesis and decreases in eNOS expression and NO/cGMP production in cultured human umbilical vein endothelial cells (HUVECs). Similar effects of aspirin were also observed in HUVECs treated with H 2 O 2 . The preventive effects of aspirin was associated with the inhibition of nuclear factor-κB (NF-κB)-dependent MIR155HG (miR-155 host gene) expression. Aspirin recovered the TNF-α-mediated decrease in wild-type, but not mutant, eNOS 3′-untranslated region reporter activity, whose effect was blocked by miR-155 mimic. Moreover, aspirin prevented TNF-α-mediated endothelial cell dysfunction associated with impaired vasorelaxation, angiogenesis, and trophoblast invasion, and the preventive effects were blocked by miR-155 mimic or an eNOS inhibitor. Aspirin rescued TNF-α-mediated eNOS downregulation coupled with endothelial dysfunction by inhibiting NF-κB-dependent transcriptional miR-155 biogenesis. Thus, the redox-sensitive NF-κB/miR-155/eNOS axis may be crucial in the pathogenesis of vascular disorders including preeclampsia.",
author = "Joohwan Kim and Lee, {Kyu Sun} and Kim, {Ji Hee} and Lee, {Dong Keon} and Minsik Park and Seunghwan Choi and Wonjin Park and Suji Kim and Choi, {Yoon Kyoung} and Hwang, {Jong Yun} and Jongseon Choe and Won, {Moo Ho} and Dooil Jeoung and Hansoo Lee and Sungwoo Ryoo and Ha, {Kwon Soo} and Young-Guen Kwon and Kim, {Young Myeong}",
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Kim, J, Lee, KS, Kim, JH, Lee, DK, Park, M, Choi, S, Park, W, Kim, S, Choi, YK, Hwang, JY, Choe, J, Won, MH, Jeoung, D, Lee, H, Ryoo, S, Ha, KS, Kwon, Y-G & Kim, YM 2017, 'Aspirin prevents TNF-α-induced endothelial cell dysfunction by regulating the NF-κB-dependent miR-155/eNOS pathway: Role of a miR-155/eNOS axis in preeclampsia', Free Radical Biology and Medicine, vol. 104, pp. 185-198. https://doi.org/10.1016/j.freeradbiomed.2017.01.010

Aspirin prevents TNF-α-induced endothelial cell dysfunction by regulating the NF-κB-dependent miR-155/eNOS pathway : Role of a miR-155/eNOS axis in preeclampsia. / Kim, Joohwan; Lee, Kyu Sun; Kim, Ji Hee; Lee, Dong Keon; Park, Minsik; Choi, Seunghwan; Park, Wonjin; Kim, Suji; Choi, Yoon Kyoung; Hwang, Jong Yun; Choe, Jongseon; Won, Moo Ho; Jeoung, Dooil; Lee, Hansoo; Ryoo, Sungwoo; Ha, Kwon Soo; Kwon, Young-Guen; Kim, Young Myeong.

In: Free Radical Biology and Medicine, Vol. 104, 01.03.2017, p. 185-198.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aspirin prevents TNF-α-induced endothelial cell dysfunction by regulating the NF-κB-dependent miR-155/eNOS pathway

T2 - Role of a miR-155/eNOS axis in preeclampsia

AU - Kim, Joohwan

AU - Lee, Kyu Sun

AU - Kim, Ji Hee

AU - Lee, Dong Keon

AU - Park, Minsik

AU - Choi, Seunghwan

AU - Park, Wonjin

AU - Kim, Suji

AU - Choi, Yoon Kyoung

AU - Hwang, Jong Yun

AU - Choe, Jongseon

AU - Won, Moo Ho

AU - Jeoung, Dooil

AU - Lee, Hansoo

AU - Ryoo, Sungwoo

AU - Ha, Kwon Soo

AU - Kwon, Young-Guen

AU - Kim, Young Myeong

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Preeclampsia is an inflammatory disease with endothelial cell dysfunction that occurs via decreased endothelial nitric oxide synthase/nitric oxide (eNOS/NO) activity. Aspirin reduces the incidence of hypertensive pregnancy complications. However, the underlying mechanism has not been clearly explained. Here, we found that tumor necrosis factor (TNF)-α, microRNA (miR)−155, and eNOS levels as well as endothelial redox phenotype were differentially regulated in preeclamptic patients, implying the involvement of TNF-α- and redox signal-mediated miR-155 biogenesis and eNOS downregulation in the pathogenesis of preeclampsia. Aspirin prevented the TNF-α-mediated increase in miR-155 biogenesis and decreases in eNOS expression and NO/cGMP production in cultured human umbilical vein endothelial cells (HUVECs). Similar effects of aspirin were also observed in HUVECs treated with H 2 O 2 . The preventive effects of aspirin was associated with the inhibition of nuclear factor-κB (NF-κB)-dependent MIR155HG (miR-155 host gene) expression. Aspirin recovered the TNF-α-mediated decrease in wild-type, but not mutant, eNOS 3′-untranslated region reporter activity, whose effect was blocked by miR-155 mimic. Moreover, aspirin prevented TNF-α-mediated endothelial cell dysfunction associated with impaired vasorelaxation, angiogenesis, and trophoblast invasion, and the preventive effects were blocked by miR-155 mimic or an eNOS inhibitor. Aspirin rescued TNF-α-mediated eNOS downregulation coupled with endothelial dysfunction by inhibiting NF-κB-dependent transcriptional miR-155 biogenesis. Thus, the redox-sensitive NF-κB/miR-155/eNOS axis may be crucial in the pathogenesis of vascular disorders including preeclampsia.

AB - Preeclampsia is an inflammatory disease with endothelial cell dysfunction that occurs via decreased endothelial nitric oxide synthase/nitric oxide (eNOS/NO) activity. Aspirin reduces the incidence of hypertensive pregnancy complications. However, the underlying mechanism has not been clearly explained. Here, we found that tumor necrosis factor (TNF)-α, microRNA (miR)−155, and eNOS levels as well as endothelial redox phenotype were differentially regulated in preeclamptic patients, implying the involvement of TNF-α- and redox signal-mediated miR-155 biogenesis and eNOS downregulation in the pathogenesis of preeclampsia. Aspirin prevented the TNF-α-mediated increase in miR-155 biogenesis and decreases in eNOS expression and NO/cGMP production in cultured human umbilical vein endothelial cells (HUVECs). Similar effects of aspirin were also observed in HUVECs treated with H 2 O 2 . The preventive effects of aspirin was associated with the inhibition of nuclear factor-κB (NF-κB)-dependent MIR155HG (miR-155 host gene) expression. Aspirin recovered the TNF-α-mediated decrease in wild-type, but not mutant, eNOS 3′-untranslated region reporter activity, whose effect was blocked by miR-155 mimic. Moreover, aspirin prevented TNF-α-mediated endothelial cell dysfunction associated with impaired vasorelaxation, angiogenesis, and trophoblast invasion, and the preventive effects were blocked by miR-155 mimic or an eNOS inhibitor. Aspirin rescued TNF-α-mediated eNOS downregulation coupled with endothelial dysfunction by inhibiting NF-κB-dependent transcriptional miR-155 biogenesis. Thus, the redox-sensitive NF-κB/miR-155/eNOS axis may be crucial in the pathogenesis of vascular disorders including preeclampsia.

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