title: Hypoxia induces FoxO3a-mediated dysfunction of blood-brain barrier.
abstract: The Forkhead box O 3a (FoxO3a), a transcription factor, is known to be involve in change of endothelial permeability. During hypoxia, blood-brain barrier (BBB) permeability is increased through degradation of vascular endothelium cadherin (VE-cadherin) and clsudin-5. The hypoxia also increased mRNA levels of matrix metalloproteinase (MMP)-3/9 and promoted translocation of FoxO3a into nucleus in endothelial cells. However, little is known about the role of FoxO3a in hypoxia-induced BBB hyperpermeability. Here, we examined whether FoxO3a regulates hypoxia-induced BBB permeability through induction of MMPs. The transfection of siFoxO3a suppressed hypoxia-induced BBB hyperpermeability. The transfection of siFoxO3a also inhibited hypoxia-induced degradation of VE-cadherin and claudin-5. In addition, the transfection of siFoxO3a reduced hypoxia-induced increase of MMP-3 mRNA levels. However, transfection of siFoxO3a did not inhibits transcription of MMP-9 induced by hypoxia. Taken together, our findings suggest that FoxO3a is involved in hypoxia-induced degradation of VE-cadherin and claudin-5 through induction of MMPs indirectly.
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea; Graduate Program of Molecular Medicine, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Soo-Wang
authors.initials: SW
authors.lastname: Hyun
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea; Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: yisjung@ajou.ac.kr.
authors.forename: Yi-Sook
authors.initials: YS
authors.lastname: Jung
mesh_terms: D001812:Blood-Brain Barrier / Q000502:physiology*; D015687:Cell Hypoxia; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors
keywords: Blood–brain barrier (BBB); Forkhead box O 3a (FoxO3a); Hypoxia; Junctional complex; Matrix metalloproteinase (MMP)