Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage
•The protein level of GPX4 in brain tissues was decreased at 24 h after ICH.•Over-expression of GPX4 can alleviate brain injury induced by ICH.•Blockade ferroptosis by Ferrostatin-1 improved brain injury after ICH.•Decreased GPX4 may contribute to SBI after ICH by mediating ferroptosis. Oxidative st...
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| Veröffentlicht in: | Brain research 2018-12, Vol.1701, p.112-125 |
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| creator | Zhang, Zhuwei Wu, Yu Yuan, Shuai Zhang, Peng Zhang, Juyi Li, Haiying Li, Xiang Shen, Haitao Wang, Zhong Chen, Gang |
| description | •The protein level of GPX4 in brain tissues was decreased at 24 h after ICH.•Over-expression of GPX4 can alleviate brain injury induced by ICH.•Blockade ferroptosis by Ferrostatin-1 improved brain injury after ICH.•Decreased GPX4 may contribute to SBI after ICH by mediating ferroptosis.
Oxidative stress plays an important role in secondary brain injury (SBI) after intracerebral hemorrhage (ICH), but the underling mechanism has not been fully elucidated. Recently, the antioxidant enzyme glutathione peroxidase 4 (GPX4), has attracted increasing attention due to its ability to degrade reactive oxygen species (ROS) which are the major indicator of oxidative stress; However, the role of GPX4 in ICH has not been reported. This study was designed to investigate the changes in protein levels, as well as potential role and mechanism of GPX4 in SBI following ICH using a Sprague-Dawley (SD) rat model of ICH induced by autologous blood injection into the right basal ganglia. Firstly, GPX4 protein levels in the brain were reduced gradually and bottomed out at 24 h after ICH, compared with the Sham group. Secondly, genetic-overexpression of GPX4 effectively increased level of GPX4 in the brain, and clearly relieved neuronal dysfunction, brain edema, blood brain barrier (BBB) injury, oxidative stress and inflammation after ICH. In contrast, inhibiting GPX4 with a specific pharmacological inhibitor or genetic knockdown exacerbated SBI after ICH. Finally, Ferrostatin-1, a chemical inhibitor of ferroptosis, was used to explore the role of ferroptosis in brain injury after ICH. The results suggest that inhibiting ferroptosis can significantly alleviate SBI after ICH. In summary, our work indicated that GPX4 contributes to SBI following ICH by mediating ferroptosis. Therefore, inhibiting ferroptosis with specific inhibitors or upregulation of GPX4 may be a potential strategy to ameliorate brain injury induced by ICH. |
| doi_str_mv | 10.1016/j.brainres.2018.09.012 |
| format | Article |
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Oxidative stress plays an important role in secondary brain injury (SBI) after intracerebral hemorrhage (ICH), but the underling mechanism has not been fully elucidated. Recently, the antioxidant enzyme glutathione peroxidase 4 (GPX4), has attracted increasing attention due to its ability to degrade reactive oxygen species (ROS) which are the major indicator of oxidative stress; However, the role of GPX4 in ICH has not been reported. This study was designed to investigate the changes in protein levels, as well as potential role and mechanism of GPX4 in SBI following ICH using a Sprague-Dawley (SD) rat model of ICH induced by autologous blood injection into the right basal ganglia. Firstly, GPX4 protein levels in the brain were reduced gradually and bottomed out at 24 h after ICH, compared with the Sham group. Secondly, genetic-overexpression of GPX4 effectively increased level of GPX4 in the brain, and clearly relieved neuronal dysfunction, brain edema, blood brain barrier (BBB) injury, oxidative stress and inflammation after ICH. In contrast, inhibiting GPX4 with a specific pharmacological inhibitor or genetic knockdown exacerbated SBI after ICH. Finally, Ferrostatin-1, a chemical inhibitor of ferroptosis, was used to explore the role of ferroptosis in brain injury after ICH. The results suggest that inhibiting ferroptosis can significantly alleviate SBI after ICH. In summary, our work indicated that GPX4 contributes to SBI following ICH by mediating ferroptosis. Therefore, inhibiting ferroptosis with specific inhibitors or upregulation of GPX4 may be a potential strategy to ameliorate brain injury induced by ICH.</description><identifier>ISSN: 0006-8993</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/j.brainres.2018.09.012</identifier><identifier>PMID: 30205109</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Ferroptosis ; Glutathione peroxidase 4 ; Intracerebral hemorrhage ; Reactive oxygen species ; Secondary brain injury</subject><ispartof>Brain research, 2018-12, Vol.1701, p.112-125</ispartof><rights>2018 Elsevier B.V.</rights><rights>Copyright © 2018 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c368t-733f694d04c88f1aaf836e44fadb9a2a1480789c65b53532d604ed74f2bbef053</citedby><cites>FETCH-LOGICAL-c368t-733f694d04c88f1aaf836e44fadb9a2a1480789c65b53532d604ed74f2bbef053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006899318304694$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30205109$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Zhuwei</creatorcontrib><creatorcontrib>Wu, Yu</creatorcontrib><creatorcontrib>Yuan, Shuai</creatorcontrib><creatorcontrib>Zhang, Peng</creatorcontrib><creatorcontrib>Zhang, Juyi</creatorcontrib><creatorcontrib>Li, Haiying</creatorcontrib><creatorcontrib>Li, Xiang</creatorcontrib><creatorcontrib>Shen, Haitao</creatorcontrib><creatorcontrib>Wang, Zhong</creatorcontrib><creatorcontrib>Chen, Gang</creatorcontrib><title>Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage</title><title>Brain research</title><addtitle>Brain Res</addtitle><description>•The protein level of GPX4 in brain tissues was decreased at 24 h after ICH.•Over-expression of GPX4 can alleviate brain injury induced by ICH.•Blockade ferroptosis by Ferrostatin-1 improved brain injury after ICH.•Decreased GPX4 may contribute to SBI after ICH by mediating ferroptosis.
Oxidative stress plays an important role in secondary brain injury (SBI) after intracerebral hemorrhage (ICH), but the underling mechanism has not been fully elucidated. Recently, the antioxidant enzyme glutathione peroxidase 4 (GPX4), has attracted increasing attention due to its ability to degrade reactive oxygen species (ROS) which are the major indicator of oxidative stress; However, the role of GPX4 in ICH has not been reported. This study was designed to investigate the changes in protein levels, as well as potential role and mechanism of GPX4 in SBI following ICH using a Sprague-Dawley (SD) rat model of ICH induced by autologous blood injection into the right basal ganglia. Firstly, GPX4 protein levels in the brain were reduced gradually and bottomed out at 24 h after ICH, compared with the Sham group. Secondly, genetic-overexpression of GPX4 effectively increased level of GPX4 in the brain, and clearly relieved neuronal dysfunction, brain edema, blood brain barrier (BBB) injury, oxidative stress and inflammation after ICH. In contrast, inhibiting GPX4 with a specific pharmacological inhibitor or genetic knockdown exacerbated SBI after ICH. Finally, Ferrostatin-1, a chemical inhibitor of ferroptosis, was used to explore the role of ferroptosis in brain injury after ICH. The results suggest that inhibiting ferroptosis can significantly alleviate SBI after ICH. In summary, our work indicated that GPX4 contributes to SBI following ICH by mediating ferroptosis. Therefore, inhibiting ferroptosis with specific inhibitors or upregulation of GPX4 may be a potential strategy to ameliorate brain injury induced by ICH.</description><subject>Ferroptosis</subject><subject>Glutathione peroxidase 4</subject><subject>Intracerebral hemorrhage</subject><subject>Reactive oxygen species</subject><subject>Secondary brain injury</subject><issn>0006-8993</issn><issn>1872-6240</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqFUcFu1TAQtBCIvhZ-ofKRS9K1nTjxDVRBQarEBc6W46xf_JTEwXYQ_AGfjdvXcuW0mtXMjnaGkGsGNQMmb071EI1fI6aaA-trUDUw_oIcWN_xSvIGXpIDAMiqV0pckMuUTgUKoeA1uRDAoWWgDuTP3bxnkycfVqQbxvDLjyYhbehmYvbWbyZjon6lCW1YRxN_00fnsjrtBeQphv040QVHb7Jfj9RhjGHLIflHnaHRZLqEEWcaXNnkaCxGLFdmOuESYpzMEd-QV87MCd8-zSvy_dPHb7efq_uvd19uP9xXVsg-V50QTqpmhMb2vWPGuF5IbBpnxkEZbljTQ9crK9uhFa3go4QGx65xfBjQQSuuyLvz3S2GHzumrBefLM6zWTHsSXMGXHFQnSpUeabaGFKK6PQW_VIS0Az0Qwv6pJ9b0A8taFC6tFCE108e-1By-Sd7jr0Q3p8JWD796THqZD2utmQY0WY9Bv8_j7_YJ5-t</recordid><startdate>20181215</startdate><enddate>20181215</enddate><creator>Zhang, Zhuwei</creator><creator>Wu, Yu</creator><creator>Yuan, Shuai</creator><creator>Zhang, Peng</creator><creator>Zhang, Juyi</creator><creator>Li, Haiying</creator><creator>Li, Xiang</creator><creator>Shen, Haitao</creator><creator>Wang, Zhong</creator><creator>Chen, Gang</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20181215</creationdate><title>Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage</title><author>Zhang, Zhuwei ; Wu, Yu ; Yuan, Shuai ; Zhang, Peng ; Zhang, Juyi ; Li, Haiying ; Li, Xiang ; Shen, Haitao ; Wang, Zhong ; Chen, Gang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c368t-733f694d04c88f1aaf836e44fadb9a2a1480789c65b53532d604ed74f2bbef053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Ferroptosis</topic><topic>Glutathione peroxidase 4</topic><topic>Intracerebral hemorrhage</topic><topic>Reactive oxygen species</topic><topic>Secondary brain injury</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Zhuwei</creatorcontrib><creatorcontrib>Wu, Yu</creatorcontrib><creatorcontrib>Yuan, Shuai</creatorcontrib><creatorcontrib>Zhang, Peng</creatorcontrib><creatorcontrib>Zhang, Juyi</creatorcontrib><creatorcontrib>Li, Haiying</creatorcontrib><creatorcontrib>Li, Xiang</creatorcontrib><creatorcontrib>Shen, Haitao</creatorcontrib><creatorcontrib>Wang, Zhong</creatorcontrib><creatorcontrib>Chen, Gang</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Brain research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Zhuwei</au><au>Wu, Yu</au><au>Yuan, Shuai</au><au>Zhang, Peng</au><au>Zhang, Juyi</au><au>Li, Haiying</au><au>Li, Xiang</au><au>Shen, Haitao</au><au>Wang, Zhong</au><au>Chen, Gang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage</atitle><jtitle>Brain research</jtitle><addtitle>Brain Res</addtitle><date>2018-12-15</date><risdate>2018</risdate><volume>1701</volume><spage>112</spage><epage>125</epage><pages>112-125</pages><issn>0006-8993</issn><eissn>1872-6240</eissn><abstract>•The protein level of GPX4 in brain tissues was decreased at 24 h after ICH.•Over-expression of GPX4 can alleviate brain injury induced by ICH.•Blockade ferroptosis by Ferrostatin-1 improved brain injury after ICH.•Decreased GPX4 may contribute to SBI after ICH by mediating ferroptosis.
Oxidative stress plays an important role in secondary brain injury (SBI) after intracerebral hemorrhage (ICH), but the underling mechanism has not been fully elucidated. Recently, the antioxidant enzyme glutathione peroxidase 4 (GPX4), has attracted increasing attention due to its ability to degrade reactive oxygen species (ROS) which are the major indicator of oxidative stress; However, the role of GPX4 in ICH has not been reported. This study was designed to investigate the changes in protein levels, as well as potential role and mechanism of GPX4 in SBI following ICH using a Sprague-Dawley (SD) rat model of ICH induced by autologous blood injection into the right basal ganglia. Firstly, GPX4 protein levels in the brain were reduced gradually and bottomed out at 24 h after ICH, compared with the Sham group. Secondly, genetic-overexpression of GPX4 effectively increased level of GPX4 in the brain, and clearly relieved neuronal dysfunction, brain edema, blood brain barrier (BBB) injury, oxidative stress and inflammation after ICH. In contrast, inhibiting GPX4 with a specific pharmacological inhibitor or genetic knockdown exacerbated SBI after ICH. Finally, Ferrostatin-1, a chemical inhibitor of ferroptosis, was used to explore the role of ferroptosis in brain injury after ICH. The results suggest that inhibiting ferroptosis can significantly alleviate SBI after ICH. In summary, our work indicated that GPX4 contributes to SBI following ICH by mediating ferroptosis. Therefore, inhibiting ferroptosis with specific inhibitors or upregulation of GPX4 may be a potential strategy to ameliorate brain injury induced by ICH.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>30205109</pmid><doi>10.1016/j.brainres.2018.09.012</doi><tpages>14</tpages></addata></record> |
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| subjects | Ferroptosis Glutathione peroxidase 4 Intracerebral hemorrhage Reactive oxygen species Secondary brain injury |
| title | Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage |
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