title: β-Dystroglycan cleavage by matrix metalloproteinase-2/-9 disturbs aquaporin-4 polarization and influences brain edema in acute cerebral ischemia.
abstract: Dystroglycan (DG) is widely expressed in various tissues, and throughout the cerebral microvasculature. It consists of two subunits, α-DG and β-DG, and the cleavage of the latter by matrix metalloproteinase (MMP)-2 and -9 underlies a number of physiological and pathological processes. However, the involvement of MMP-2/-9-mediated β-DG cleavage in cerebral ischemia remains uncertain. In astrocytes, DG is crucial for maintaining the polarization of aquaporin-4 (AQP4), which plays a role in the regulation of cytotoxic and vasogenic edema. The present study aimed to explore the effects of MMP-2/-9-mediated β-DG cleavage on AQP4 polarization and brain edema in acute cerebral ischemia. A model of cerebral ischemia was established via permanent middle cerebral artery occlusion (pMCAO) in male C57BL/6 mice. Western blotting, real-time polymerase chain reaction (PCR), immunohistochemical staining, immunofluorescent staining, electron microscopy, and light microscopy were used. Captopril was applied as a selective MMP-2/-9 inhibitor. Recombinant mouse MMP (rmMMP)-2 and -9 were used in an in vitro cleavage experiment. The present study demonstrated evidence of β-DG cleavage by MMP-2/-9 in pMCAO mouse brains; this cleavage was implicated in AQP4 redistribution and brain edema in cerebral ischemia. In addition, captopril exacerbated cytotoxic edema and ameliorated vasogenic edema at 24h after pMCAO, and alleviated brain edema and neurological deficit at 48h and 72h. In conclusion, this study provides novel insight into the effects of MMP-2/-9-mediated β-DG cleavage in acute cerebral ischemia. Such findings might facilitate the development of a therapeutic strategy for the optimization of MMP-2/-9 targeted treatment in cerebral ischemia.
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: D
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Neurology, the First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin, 150001 Heilongjiang, PR China. Electronic address: lgzhyd1962@163.com.
authors.forename: G
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000648:ultrastructure; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002216:Captopril / Q000008:administration & dosage; D049030:Dystroglycans / Q000378:metabolism*; D004487:Edema / Q000209:etiology / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D061965:Matrix Metalloproteinase Inhibitors; D049030:Dystroglycans; D002216:Captopril; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: aquaporin-4; brain edema; cerebral ischemia; matrix metalloproteinase-2; matrix metalloproteinase-9; β-dystroglycan