title: 17β-Estradiol Ameliorates Tight Junction Disruption via Repression of MMP Transcription.
abstract: The blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB) formed by capillary endothelial cells provides a physical wall between the central nervous system (CNS) and circulating blood with highly selective permeability. BBB/BSCB disruption by activation of matrix metalloproteinases (MMPs) has been shown to result in further neurological damage after CNS injury. Recently it has been discovered that estrogen attenuates BBB/BSCB disruption in in vitro and in vivo models. However, the molecular mechanism underlying the estrogen-mediated attenuation of BBB/BSCB disruption has not been elucidated fully. In the present study, we found that 17β-estradiol (E2) suppresses nuclear factor-κB-dependent MMP-1b, MMP-2, MMP-3, MMP-9, MMP-10, and MMP-13 gene activation in microvessel endothelial bEnd.3 cells subjected to oxygen and glucose deprivation/reperfusion injury. E2 induced the recruitment of ERα and nuclear receptor corepressor to the nuclear factor-κB binding site on the MMPs' gene promoters. Consistently, ER antagonist ICI 182.780 showed opposite effects of E2. We further found that E2 attenuates tight junction disruption through the decreased degradation of tight junction proteins in bEnd.3 cells subjected to oxygen and glucose deprivation-reperfusion injury. In addition, E2 suppressed the up-regulation of MMP expression, leading to a decreased BSCB disruption in the injured spinal cord. In conclusion, we discovered the molecular mechanism underlying the protective role of estrogenin BBB/BSCB disruption using an in vitro and in vivo model. Our study suggests that estrogens may provide a potential therapeutic intervention for preserving BBB/BSCB integrity after CNS injury.
authors.affiliation: Department of Life Science (W.N., W.-S.K., B.-G.J.), Sogang University, Seoul 121-742, Korea; and Age-Related and Brain Diseases Research Center (J.Y.L., T.Y.Y.) and Department of Biochemistry and Molecular Biology (T.Y.Y.), School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Wonho
authors.initials: W
authors.lastname: Na
authors.affiliation: Department of Life Science (W.N., W.-S.K., B.-G.J.), Sogang University, Seoul 121-742, Korea; and Age-Related and Brain Diseases Research Center (J.Y.L., T.Y.Y.) and Department of Biochemistry and Molecular Biology (T.Y.Y.), School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Jee Youn
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Life Science (W.N., W.-S.K., B.-G.J.), Sogang University, Seoul 121-742, Korea; and Age-Related and Brain Diseases Research Center (J.Y.L., T.Y.Y.) and Department of Biochemistry and Molecular Biology (T.Y.Y.), School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Won-Sun
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Life Science (W.N., W.-S.K., B.-G.J.), Sogang University, Seoul 121-742, Korea; and Age-Related and Brain Diseases Research Center (J.Y.L., T.Y.Y.) and Department of Biochemistry and Molecular Biology (T.Y.Y.), School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Tae Young
authors.initials: TY
authors.lastname: Yune
authors.affiliation: Department of Life Science (W.N., W.-S.K., B.-G.J.), Sogang University, Seoul 121-742, Korea; and Age-Related and Brain Diseases Research Center (J.Y.L., T.Y.Y.) and Department of Biochemistry and Molecular Biology (T.Y.Y.), School of Medicine, Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Bong-Gun
authors.initials: BG
authors.lastname: Ju
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology; D002460:Cell Line; D017097:Electric Impedance; D042783:Endothelial Cells / Q000166:cytology; D004789:Enzyme Activation; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077267:Fulvestrant; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000077267:Fulvestrant; D004958:Estradiol; D020782:Matrix Metalloproteinases