Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury
Background The postmitotic state of adult cardiomyocytes, maintained by the cell cycle repressor Rbl2 (retinoblastoma‐like 2), is associated with considerable resistance to apoptosis. However, whether Rbl2 regulates cardiomyocyte apoptosis remains unknown. Methods and Results Here, we show that abla...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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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.121.024764 |
| _version_ | 1797857421355384832 |
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| author | Jingrui Chen Peng Xia Yuening Liu Clark Kogan Zhaokang Cheng |
| author_facet | Jingrui Chen Peng Xia Yuening Liu Clark Kogan Zhaokang Cheng |
| author_sort | Jingrui Chen |
| collection | DOAJ |
| description | Background The postmitotic state of adult cardiomyocytes, maintained by the cell cycle repressor Rbl2 (retinoblastoma‐like 2), is associated with considerable resistance to apoptosis. However, whether Rbl2 regulates cardiomyocyte apoptosis remains unknown. Methods and Results Here, we show that ablation of Rbl2 increased cardiomyocyte apoptosis following acute myocardial ischemia/reperfusion injury, leading to diminished cardiac function and exaggerated ventricular remodeling in the long term. Mechanistically, ischemia/reperfusion induced expression of the proapoptotic protein BCL2 interacting protein 3 (Bnip3), which was augmented by deletion of Rbl2. Because the Bnip3 promoter contains an adenoviral early region 2 binding factor (E2F)‐binding site, we further showed that loss of Rbl2 upregulated the transcriptional activator E2F1 but downregulated the transcriptional repressor E2F4. In cultured cardiomyocytes, treatment with H2O2 markedly increased the levels of E2F1 and Bnip3, resulting in mitochondrial depolarization and apoptosis. Depletion of Rbl2 significantly augmented H2O2‐induced mitochondrial damage and apoptosis in vitro. Conclusions Rbl2 deficiency enhanced E2F1‐mediated Bnip3 expression, resulting in aggravated cardiomyocyte apoptosis and ischemia/reperfusion injury. Our results uncover a novel antiapoptotic role for Rbl2 in cardiomyocytes, suggesting that the cell cycle machinery may directly regulate apoptosis in postmitotic cardiomyocytes. These findings may be exploited to develop new strategies to limit ischemia/reperfusion injury in the treatment of acute myocardial infarction. |
| first_indexed | 2024-04-09T20:56:26Z |
| format | Article |
| id | doaj.art-74698b02997c42aabd6e72a3116195bc |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-09T20:56:26Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-74698b02997c42aabd6e72a3116195bc2023-03-29T18:35:57ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-10-01111910.1161/JAHA.121.024764Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion InjuryJingrui Chen0Peng Xia1Yuening Liu2Clark Kogan3Zhaokang Cheng4Department of Pharmaceutical Sciences Washington State University Spokane WashingtonDepartment of Pharmaceutical Sciences Washington State University Spokane WashingtonDepartment of Pharmaceutical Sciences Washington State University Spokane WashingtonDepartment of Pharmaceutical Sciences Washington State University Spokane WashingtonDepartment of Pharmaceutical Sciences Washington State University Spokane WashingtonBackground The postmitotic state of adult cardiomyocytes, maintained by the cell cycle repressor Rbl2 (retinoblastoma‐like 2), is associated with considerable resistance to apoptosis. However, whether Rbl2 regulates cardiomyocyte apoptosis remains unknown. Methods and Results Here, we show that ablation of Rbl2 increased cardiomyocyte apoptosis following acute myocardial ischemia/reperfusion injury, leading to diminished cardiac function and exaggerated ventricular remodeling in the long term. Mechanistically, ischemia/reperfusion induced expression of the proapoptotic protein BCL2 interacting protein 3 (Bnip3), which was augmented by deletion of Rbl2. Because the Bnip3 promoter contains an adenoviral early region 2 binding factor (E2F)‐binding site, we further showed that loss of Rbl2 upregulated the transcriptional activator E2F1 but downregulated the transcriptional repressor E2F4. In cultured cardiomyocytes, treatment with H2O2 markedly increased the levels of E2F1 and Bnip3, resulting in mitochondrial depolarization and apoptosis. Depletion of Rbl2 significantly augmented H2O2‐induced mitochondrial damage and apoptosis in vitro. Conclusions Rbl2 deficiency enhanced E2F1‐mediated Bnip3 expression, resulting in aggravated cardiomyocyte apoptosis and ischemia/reperfusion injury. Our results uncover a novel antiapoptotic role for Rbl2 in cardiomyocytes, suggesting that the cell cycle machinery may directly regulate apoptosis in postmitotic cardiomyocytes. These findings may be exploited to develop new strategies to limit ischemia/reperfusion injury in the treatment of acute myocardial infarction.https://www.ahajournals.org/doi/10.1161/JAHA.121.024764apoptosiscardiac myocytescell cyclecell deathcyclin‐dependent kinasemyocardial infarction |
| spellingShingle | Jingrui Chen Peng Xia Yuening Liu Clark Kogan Zhaokang Cheng Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease apoptosis cardiac myocytes cell cycle cell death cyclin‐dependent kinase myocardial infarction |
| title | Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury |
| title_full | Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury |
| title_fullStr | Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury |
| title_full_unstemmed | Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury |
| title_short | Loss of Rbl2 (Retinoblastoma‐Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury |
| title_sort | loss of rbl2 retinoblastoma like 2 exacerbates myocardial ischemia reperfusion injury |
| topic | apoptosis cardiac myocytes cell cycle cell death cyclin‐dependent kinase myocardial infarction |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.024764 |
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