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 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.
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Joohwan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Kyu-Sun
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Dong-Keon
authors.initials: DK
authors.lastname: Lee
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Minsik
authors.initials: M
authors.lastname: Park
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Seunghwan
authors.initials: S
authors.lastname: Choi
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Wonjin
authors.initials: W
authors.lastname: Park
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Suji
authors.initials: S
authors.lastname: Kim
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Departments of Obstetrics and Gynecology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Jong Yun
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Departments of Immunology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
authors.affiliation: Departments of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Departments of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
authors.affiliation: Departments of Biology, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Departments of Biology, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Ryoo
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: Departments of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341, South Korea. Electronic address: ymkim@kangwon.ac.kr.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000328:Adult; D001241:Aspirin / Q000008:administration & dosage*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D001241:Aspirin
keywords: Aspirin; ENOS; Endothelial dysfunction; MiRNA-155; NF-κB; ROS