title: Caveolin-1 is a checkpoint regulator in hypoxia-induced astrocyte apoptosis via Ras/Raf/ERK pathway.
abstract: Astrocytes, the most numerous cells in the human brain, play a central role in the metabolic homeostasis following hypoxic injury. Caveolin-1 (Cav-1), a transmembrane scaffolding protein, has been shown to converge prosurvival signaling in the central nerve system. The present study aimed to investigate the role of Cav-1 in the hypoxia-induced astrocyte injury. We also examined how Cav-1 alleviates apoptotic astrocyte death. To this end, primary astrocytes were exposed to oxygen-glucose deprivation (OGD) for 6 h and a subsequent 24-h reoxygenation to mimic hypoxic injury. OGD significantly reduced Cav-1 expression. Downregulation of Cav-1 using Cav-1 small interfering RNA dramatically worsened astrocyte cell damage and impaired cellular glutamate uptake after OGD, whereas overexpression of Cav-1 with Cav-1 scaffolding domain peptide attenuated OGD-induced cell apoptosis. Mechanistically, the expressions of Ras-GTP, phospho-Raf, and phospho-ERK were sequestered in Cav-1 small interfering RNA-treated astrocytes, yet were stimulated after supplementation with caveolin peptide. MEK/ERK inhibitor U0126 remarkably blocked the Cav-1-induced counteraction against apoptosis following hypoxia, indicating Ras/Raf/ERK pathway is required for the Cav-1's prosurvival role. Together, these findings support Cav-1 as a checkpoint for the in hypoxia-induced astrocyte apoptosis and warrant further studies targeting Cav-1 to treat hypoxic-ischemic brain injury.
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Lili
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Liumin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China; and.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Neurology, the Central Hospital of Shaoyang, Shaoyang, Hunan Province, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Lulu
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Minmin
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Wusheng
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China;
authors.forename: Ruidong
authors.initials: R
authors.lastname: Ye
authors.affiliation: Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China; xfliu2@vip.163.com.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection; D048490:raf Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C495537:Cav1 protein, rat; D051242:Caveolin 1; D047428:Protein Kinase Inhibitors; D018698:Glutamic Acid; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D005947:Glucose
keywords: ERK; astrocytes; caveolin-1; oxygen-glucose deprivation