Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein
Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activa...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2306 |
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| author | Mei-Han Kao Chien-Yu Huang Wai-Mui Cheung Yu-Ting Yan Jin-Jer Chen Yuan-Soon Ho Chung Y. Hsu Teng-Nan Lin |
| author_facet | Mei-Han Kao Chien-Yu Huang Wai-Mui Cheung Yu-Ting Yan Jin-Jer Chen Yuan-Soon Ho Chung Y. Hsu Teng-Nan Lin |
| author_sort | Mei-Han Kao |
| collection | DOAJ |
| description | Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment. |
| first_indexed | 2024-03-11T09:41:56Z |
| format | Article |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:41:56Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-80fcb0973d40482d9ff20fb34ec044cb2023-11-16T16:55:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243230610.3390/ijms24032306Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator ProteinMei-Han Kao0Chien-Yu Huang1Wai-Mui Cheung2Yu-Ting Yan3Jin-Jer Chen4Yuan-Soon Ho5Chung Y. Hsu6Teng-Nan Lin7Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11529, TaiwanDepartment of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei 11529, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei 11529, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei 11529, TaiwanSchool of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Biomedical Sciences, China Medical University, Taichung 404327, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei 11529, TaiwanActivating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3→CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3→CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment.https://www.mdpi.com/1422-0067/24/3/2306strokeapoptosisAkt/PKBATF3CTMPgene regulation |
| spellingShingle | Mei-Han Kao Chien-Yu Huang Wai-Mui Cheung Yu-Ting Yan Jin-Jer Chen Yuan-Soon Ho Chung Y. Hsu Teng-Nan Lin Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein International Journal of Molecular Sciences stroke apoptosis Akt/PKB ATF3 CTMP gene regulation |
| title | Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein |
| title_full | Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein |
| title_fullStr | Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein |
| title_full_unstemmed | Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein |
| title_short | Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein |
| title_sort | activating transcription factor 3 diminishes ischemic cerebral infarct and behavioral deficit by downregulating carboxyl terminal modulator protein |
| topic | stroke apoptosis Akt/PKB ATF3 CTMP gene regulation |
| url | https://www.mdpi.com/1422-0067/24/3/2306 |
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