Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke
BackgroundStroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathoph...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2017-10-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.117.007236 |
| _version_ | 1819178553169674240 |
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| author | Ying Tang Yu‐Hui Lin Huan‐Yu Ni Jian Dong Hong‐Jin Yuan Yu Zhang Hai‐Ying Liang Meng‐Cheng Yao Qi‐Gang Zhou Hai‐Yin Wu Lei Chang Chun‐Xia Luo Dong‐Ya Zhu |
| author_facet | Ying Tang Yu‐Hui Lin Huan‐Yu Ni Jian Dong Hong‐Jin Yuan Yu Zhang Hai‐Ying Liang Meng‐Cheng Yao Qi‐Gang Zhou Hai‐Yin Wu Lei Chang Chun‐Xia Luo Dong‐Ya Zhu |
| author_sort | Ying Tang |
| collection | DOAJ |
| description | BackgroundStroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery. Methods and ResultsFocal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout (Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone. ConclusionsOur novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke. |
| first_indexed | 2024-12-22T21:44:23Z |
| format | Article |
| id | doaj.art-e016ee3809f6489e904c36d7d70a0cb1 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-22T21:44:23Z |
| publishDate | 2017-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-e016ee3809f6489e904c36d7d70a0cb12022-12-21T18:11:32ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802017-10-0161010.1161/JAHA.117.007236Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From StrokeYing Tang0Yu‐Hui Lin1Huan‐Yu Ni2Jian Dong3Hong‐Jin Yuan4Yu Zhang5Hai‐Ying Liang6Meng‐Cheng Yao7Qi‐Gang Zhou8Hai‐Yin Wu9Lei Chang10Chun‐Xia Luo11Dong‐Ya Zhu12Institution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaInstitution of Stem Cells and Neuroregeneration, School of Pharmacy, Nanjing Medical University, Nanjing, ChinaBackgroundStroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery. Methods and ResultsFocal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout (Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone. ConclusionsOur novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.https://www.ahajournals.org/doi/10.1161/JAHA.117.007236epigeneticsfunctional recoveryhistone deacetylase 2histone deacetylase inhibitorstroke |
| spellingShingle | Ying Tang Yu‐Hui Lin Huan‐Yu Ni Jian Dong Hong‐Jin Yuan Yu Zhang Hai‐Ying Liang Meng‐Cheng Yao Qi‐Gang Zhou Hai‐Yin Wu Lei Chang Chun‐Xia Luo Dong‐Ya Zhu Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease epigenetics functional recovery histone deacetylase 2 histone deacetylase inhibitor stroke |
| title | Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke |
| title_full | Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke |
| title_fullStr | Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke |
| title_full_unstemmed | Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke |
| title_short | Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke |
| title_sort | inhibiting histone deacetylase 2 hdac2 promotes functional recovery from stroke |
| topic | epigenetics functional recovery histone deacetylase 2 histone deacetylase inhibitor stroke |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.117.007236 |
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