The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injury
IntroductionThe molecular mechanisms underlying cardioprotection against doxorubicin (DOX)-induced myocardial injury are poorly understood. Histone deacetylase 2 (HDAC2) plays a significant role in oxidative stress, apoptosis, and mitochondrial dysfunction and is implicated in many human diseases, T...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2025.1557119/full |
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| author | Jinsha Liu Jinsha Liu Wenwen Fu Xue Wang Xue Wang Zuowen Liang Fanbo Meng Fanbo Meng |
| author_facet | Jinsha Liu Jinsha Liu Wenwen Fu Xue Wang Xue Wang Zuowen Liang Fanbo Meng Fanbo Meng |
| author_sort | Jinsha Liu |
| collection | DOAJ |
| description | IntroductionThe molecular mechanisms underlying cardioprotection against doxorubicin (DOX)-induced myocardial injury are poorly understood. Histone deacetylase 2 (HDAC2) plays a significant role in oxidative stress, apoptosis, and mitochondrial dysfunction and is implicated in many human diseases, This study investigated the relationship between HDAC2 expression and DOX-induced myocardial injury using the in vivo rat model of DOX-induced cardiotoxicity and in vitro experiments with the H9c2 cardiomyocytes.MethodsThe rat model of DOX-induced myocardial injury was established by administering DOX via intraperitoneal injections. HDAC2 expression was suppressed by administering rats with sodium butyrate (SB) via intraperitoneal injections. Echocardiography measurements were performed at baseline and on day 15 post-treatment. The rats were euthanized on day 15 and cardiac tissues were harvested. The cardiac tissue samples were analyzed by hematoxylin and eosin H&E staining, immunohistochemistry, Masson staining, Sirius Red staining, TUNEL staining, and western blotting to determine the status of HDAC2 expression and myocardial apoptosis. In the vitro experiments, H9c2 cells were treated with DOX. HDAC2 expression was suppressed using sodium butyrate or transfected cells with the shRNA knockdown HDAC2 (shHDAC2). The H9c2 cells from different groups were analyzed by Rt-qPCR, CCK-8 cell viability assay, and western blotting to determine the status of HDAC2 expression and cardiomyocyte apoptosis.ResultsDOX treatment induced cardiac dysfunction in rats. The cardiac tissues of the DOX-treated rats and H9c2 cells showed significantly higher levels of HDAC2 compared to the corresponding controls. However, inhibition of HDAC2 significantly mitigated DOX-induced myocardial injury in rats. This suggested a strong association between HDAC2 expression and DOX-induced myocardial injury. In the H9c2 cells, HDAC2 knockdown by shHDAC2 alleviated DOX-induced apoptosis by enhacing AKT phosphorylation. These findings demonstrated that HDAC2 silencing protected against DOX-induced cardiomyocyte apoptosis by activating the PI3K/AKT signaling pathway.ConclusionSuppressing HDAC2 protected against DOX-induced cardiomyocyte apoptosis by activating the PI3K/AKT signaling pathway. Therefore, HDAC2 is a promising therapeutic target for mitigating DOX-induced myocardial injury. |
| format | Article |
| id | doaj-art-1d181a25294a4b70a1d7ec5d0a68bc02 |
| institution | DOAJ |
| issn | 2297-055X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj-art-1d181a25294a4b70a1d7ec5d0a68bc022025-08-20T02:45:38ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2025-02-011210.3389/fcvm.2025.15571191557119The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injuryJinsha Liu0Jinsha Liu1Wenwen Fu2Xue Wang3Xue Wang4Zuowen Liang5Fanbo Meng6Fanbo Meng7Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, ChinaJilin Provincial Engineering Laboratory for Endothelial Function and Genetic Diagnosis of Cardiovascular Disease, Jilin Provincial Cardiovascular Research Center, Changchun, ChinaDepartment of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, ChinaDepartment of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, ChinaJilin Provincial Engineering Laboratory for Endothelial Function and Genetic Diagnosis of Cardiovascular Disease, Jilin Provincial Cardiovascular Research Center, Changchun, ChinaDepartment of Andrology, The First Hospital of Jilin University, Changchun, ChinaDepartment of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, ChinaJilin Provincial Engineering Laboratory for Endothelial Function and Genetic Diagnosis of Cardiovascular Disease, Jilin Provincial Cardiovascular Research Center, Changchun, ChinaIntroductionThe molecular mechanisms underlying cardioprotection against doxorubicin (DOX)-induced myocardial injury are poorly understood. Histone deacetylase 2 (HDAC2) plays a significant role in oxidative stress, apoptosis, and mitochondrial dysfunction and is implicated in many human diseases, This study investigated the relationship between HDAC2 expression and DOX-induced myocardial injury using the in vivo rat model of DOX-induced cardiotoxicity and in vitro experiments with the H9c2 cardiomyocytes.MethodsThe rat model of DOX-induced myocardial injury was established by administering DOX via intraperitoneal injections. HDAC2 expression was suppressed by administering rats with sodium butyrate (SB) via intraperitoneal injections. Echocardiography measurements were performed at baseline and on day 15 post-treatment. The rats were euthanized on day 15 and cardiac tissues were harvested. The cardiac tissue samples were analyzed by hematoxylin and eosin H&E staining, immunohistochemistry, Masson staining, Sirius Red staining, TUNEL staining, and western blotting to determine the status of HDAC2 expression and myocardial apoptosis. In the vitro experiments, H9c2 cells were treated with DOX. HDAC2 expression was suppressed using sodium butyrate or transfected cells with the shRNA knockdown HDAC2 (shHDAC2). The H9c2 cells from different groups were analyzed by Rt-qPCR, CCK-8 cell viability assay, and western blotting to determine the status of HDAC2 expression and cardiomyocyte apoptosis.ResultsDOX treatment induced cardiac dysfunction in rats. The cardiac tissues of the DOX-treated rats and H9c2 cells showed significantly higher levels of HDAC2 compared to the corresponding controls. However, inhibition of HDAC2 significantly mitigated DOX-induced myocardial injury in rats. This suggested a strong association between HDAC2 expression and DOX-induced myocardial injury. In the H9c2 cells, HDAC2 knockdown by shHDAC2 alleviated DOX-induced apoptosis by enhacing AKT phosphorylation. These findings demonstrated that HDAC2 silencing protected against DOX-induced cardiomyocyte apoptosis by activating the PI3K/AKT signaling pathway.ConclusionSuppressing HDAC2 protected against DOX-induced cardiomyocyte apoptosis by activating the PI3K/AKT signaling pathway. Therefore, HDAC2 is a promising therapeutic target for mitigating DOX-induced myocardial injury.https://www.frontiersin.org/articles/10.3389/fcvm.2025.1557119/fullHDAC2doxorubicincardiac functionPI3K/AKTapoptosis |
| spellingShingle | Jinsha Liu Jinsha Liu Wenwen Fu Xue Wang Xue Wang Zuowen Liang Fanbo Meng Fanbo Meng The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injury Frontiers in Cardiovascular Medicine HDAC2 doxorubicin cardiac function PI3K/AKT apoptosis |
| title | The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injury |
| title_full | The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injury |
| title_fullStr | The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injury |
| title_full_unstemmed | The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injury |
| title_short | The role of HDAC2 inhibition in cardioprotection against doxorubicin-induced myocardial injury |
| title_sort | role of hdac2 inhibition in cardioprotection against doxorubicin induced myocardial injury |
| topic | HDAC2 doxorubicin cardiac function PI3K/AKT apoptosis |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2025.1557119/full |
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