Kang-Ho Choi1, Hyung-Seok Kim2, Man-Seok Park2, Joon-Tae Kim1, Ja-Hae Kim1, Kyung-Ah Cho1, Min-Cheol Lee1, Hong-Joon Lee1, Ki-Hyun Cho1. 1. From the Department of Neurology, Chonnam National University Hwasun Hospital, Hwasun, Korea (K.-H.C.); Departments of Neurology (K.-H.C., M.-S.P., J.-T.K., K.-H.C.), Forensic Medicine (H.-S.K.), Nuclear Medicine (J.-H.K.), Biochemistry and Molecular Biology (K.-A.C.), and Pathology, Chonnam National University Medical School, Gwangju, Korea (M.-C.L.); and Medical Research Institute, Chungang University College of Medicine, Seoul, Korea (H.-J.L.). 2. From the Department of Neurology, Chonnam National University Hwasun Hospital, Hwasun, Korea (K.-H.C.); Departments of Neurology (K.-H.C., M.-S.P., J.-T.K., K.-H.C.), Forensic Medicine (H.-S.K.), Nuclear Medicine (J.-H.K.), Biochemistry and Molecular Biology (K.-A.C.), and Pathology, Chonnam National University Medical School, Gwangju, Korea (M.-C.L.); and Medical Research Institute, Chungang University College of Medicine, Seoul, Korea (H.-J.L.). veritas@jnu.ac.kr mspark@chonnam.ac.kr.
Abstract
BACKGROUND AND PURPOSE: Most patients with cerebral infarction die of brain edema because of the breakdown of the blood-brain barrier (BBB) in ischemic tissue. Caveolins (a group of proteins) are key modulators of vascular permeability; however, a direct role of caveolin-1 (Cav-1) in the regulation of BBB permeability during ischemic injury has yet to be identified. METHODS: Cav-1 expression was measured by immunoblotting after photothrombotic ischemia. A direct functional role of Cav-1 in cerebral edema and BBB permeability during cerebral ischemia was investigated by genetic manipulation (gene disruption and re-expression) of Cav-1 protein expression in mice. RESULTS: There was a significant correlation between the extent of BBB disruption and the Cav-1 expression. In Cav-1-deficient (Cav-1(-/-)) mice, the extent of BBB disruption after cerebral ischemia was increased compared with wild-type (Cav-1(+/+)) mice, whereas the increase in cerebral edema volume was ameliorated by lentiviral-mediated re-expression of Cav-1. Furthermore, Cav-1(-/-) mice had significantly higher degradation of tight junction proteins and proteolytic activity of matrix metalloproteinase than Cav-1(+/+) mice. Conversely, re-expression of Cav-1 in Cav-1(-/-) mice restored tight junction protein expression and reduced matrix metalloproteinase proteolytic activity. CONCLUSIONS: These results indicate that Cav-1 is a critical determinant of BBB permeability. Strategies for regulating Cav-1 represent a novel therapeutic approach to controlling BBB disruption and subsequent neurological deterioration during cerebral ischemia.
BACKGROUND AND PURPOSE: Most patients with cerebral infarction die of brain edema because of the breakdown of the blood-brain barrier (BBB) in ischemic tissue. Caveolins (a group of proteins) are key modulators of vascular permeability; however, a direct role of caveolin-1 (Cav-1) in the regulation of BBB permeability during ischemic injury has yet to be identified. METHODS:Cav-1 expression was measured by immunoblotting after photothrombotic ischemia. A direct functional role of Cav-1 in cerebral edema and BBB permeability during cerebral ischemia was investigated by genetic manipulation (gene disruption and re-expression) of Cav-1 protein expression in mice. RESULTS: There was a significant correlation between the extent of BBB disruption and the Cav-1 expression. In Cav-1-deficient (Cav-1(-/-)) mice, the extent of BBB disruption after cerebral ischemia was increased compared with wild-type (Cav-1(+/+)) mice, whereas the increase in cerebral edema volume was ameliorated by lentiviral-mediated re-expression of Cav-1. Furthermore, Cav-1(-/-) mice had significantly higher degradation of tight junction proteins and proteolytic activity of matrix metalloproteinase than Cav-1(+/+) mice. Conversely, re-expression of Cav-1 in Cav-1(-/-) mice restored tight junction protein expression and reduced matrix metalloproteinase proteolytic activity. CONCLUSIONS: These results indicate that Cav-1 is a critical determinant of BBB permeability. Strategies for regulating Cav-1 represent a novel therapeutic approach to controlling BBB disruption and subsequent neurological deterioration during cerebral ischemia.
Authors: Carme Gubern-Mérida; Pau Comajoan; Gemma Huguet; Isaac García-Yebenes; Ignacio Lizasoain; María Angeles Moro; Irene Puig-Parnau; Juan Manuel Sánchez; Joaquín Serena; Elisabet Kádár; Mar Castellanos Journal: Mol Neurobiol Date: 2022-01-05 Impact factor: 5.590
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