title: Hypoxia-controlled matrix metalloproteinase-9 hyperexpression promotes behavioral recovery after ischemia.
abstract: Matrix metalloproteinase-9 (MMP-9) plays a beneficial role in the sub-acute phase after ischemic stroke. However, unrestrained MMP-9 may disrupt the blood-brain barrier (BBB), which has limited its use for the treatment of brain ischemia. In the present study, we constructed lentivirus mediated hypoxia-controlled MMP-9 expression and explored its role after stroke. Hypoxia response element (HRE) was used to confine MMP-9 expression only to the hypoxic region of mouse brain after 120-min transient middle cerebral artery occlusion. Lentiviruses were injected into the peri-infarct area on day 7 after transient ischemia. We found hyperexpression of exogenous HRE-MMP-9 under the control of hypoxia, and its expression was mainly located in neurons and astrocytes without aggravation of BBB damage compared to the CMV group. Furthermore, mice in the HRE-MMP-9 group showed the best behavioral recovery compared with the normal saline, GFP, and SB-3CT groups. Therefore, hypoxia-controlled MMP-9 hyperexpression during the sub-acute phase of ischemia may provide a novel promising approach of gene therapy for stroke.
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.|Neuroscience and Neuroengineering Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.|Neuroscience and Neuroengineering Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Mu
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.|Neuroscience and Neuroengineering Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Neuroscience and Neuroengineering Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Yongting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. gyyang0626@gmail.com.|Neuroscience and Neuroengineering Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China. gyyang0626@gmail.com.
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
authors.affiliation: Neuroscience and Neuroengineering Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China. zhangzhij@gmail.com.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001284:Atrophy; D001812:Blood-Brain Barrier / Q000378:metabolism*; D005822:Genetic Vectors / Q000378:metabolism; D057809:HEK293 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D016086:Lentivirus / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009043:Motor Activity; D020127:Recovery of Function; D020218:Response Elements; D045442:Rotarod Performance Test; D013450:Sulfones / Q000494:pharmacology; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D051793:Hypoxia-Inducible Factor 1; C429533:SB 3CT compound; D013450:Sulfones; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: blood-brain barrier; hypoxia response element; matrix metalloproteinase 9; stroke