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Free Radic Biol Med. 2017 Mar;104:185-198. doi: 10.1016/j.freeradbiomed.2017.01.010. Epub 2017 Jan 11.

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.

Author information

1
Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
2
Departments of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
3
Departments of Immunology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
4
Departments of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
5
Departments of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea.
6
Departments of Biology, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea.
7
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
8
Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea. Electronic address: ymkim@kangwon.ac.kr.

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 H2O2. 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.

KEYWORDS:

Aspirin; ENOS; Endothelial dysfunction; MiRNA-155; NF-κB; ROS

[Indexed for MEDLINE]

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