Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α
Abstract Background Acute myocardial infarction (AMI) is a leading cause of mortality, characterized by myocardial ischemia that induces cardiomyocyte apoptosis and subsequent cardiac dysfunction. Sirtuin 1 (Sirt1) has emerged as a key regulator of cell survival and apoptosis, particularly under hyp...
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2025-03-01
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| Online Access: | https://doi.org/10.1186/s10020-025-01155-z |
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| author | Yafen Chen Shuyao Shan Qiqi Xue Yan Ren Qihong Wu Jiawei Chen Ke Yang Jiumei Cao |
| author_facet | Yafen Chen Shuyao Shan Qiqi Xue Yan Ren Qihong Wu Jiawei Chen Ke Yang Jiumei Cao |
| author_sort | Yafen Chen |
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| description | Abstract Background Acute myocardial infarction (AMI) is a leading cause of mortality, characterized by myocardial ischemia that induces cardiomyocyte apoptosis and subsequent cardiac dysfunction. Sirtuin 1 (Sirt1) has emerged as a key regulator of cell survival and apoptosis, particularly under hypoxic conditions. Methods An AMI animal model was established via ligation of the left anterior descending (LAD) coronary artery. Gene expression in the infarcted region was evaluated at various time points. Sirt1 overexpression and control lentivirus were administered to the peri-infarct region of mice heart. After LAD ligation, assessment on myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were performed. In vitro, primary mouse cardiomyocytes subjected to hypoxia were analyzed for gene expression, while interactions among Sirt1, Phd3, and Hif-1α were explored using diverse treatment approaches. Results A significant reduction in Sirt1 and Phd3 expression, along with an increase in Hif-1α and cleaved caspase-3, was observed in a time-dependent manner post-myocardial infarction (MI). In vitro findings revealed that hypoxia decreased nuclear Sirt1 and cytoplasmic Phd3 levels while promoting a time-dependent increase in Hif-1α and cleaved caspase-3. Furthermore, Sirt1 overexpression enhanced Phd3 expression in cardiomyocytes, suppressed Hif-1α and cleaved caspase-3 levels, and alleviated hypoxia-induced cardiomyocyte apoptosis. Notably, knockdown of Phd3 negated Sirt1’s inhibitory effect on Hif-1α, whereas Hif-1α knockdown promoted Sirt1 expression. Sirt1 overexpression reduced infarct size, decreased cardiomyocyte apoptosis, and improved cardiac function. Conclusions Sirt1 effectively reduces cardiomyocyte apoptosis and myocardial infarction size while enhancing cardiac function post-MI, primarily through the Phd3/Hif-1α signaling pathway. |
| format | Article |
| id | doaj-art-dc133a9c99bc46a5a36db54ed53012cd |
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| issn | 1528-3658 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
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| series | Molecular Medicine |
| spelling | doaj-art-dc133a9c99bc46a5a36db54ed53012cd2025-08-20T02:56:16ZengBMCMolecular Medicine1528-36582025-03-0131111410.1186/s10020-025-01155-zSirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1αYafen Chen0Shuyao Shan1Qiqi Xue2Yan Ren3Qihong Wu4Jiawei Chen5Ke Yang6Jiumei Cao7Department of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Cardiology, Shanghai Ninth People’S Hospital, Shanghai Jiaotong University School of MedicineDepartment of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of MedicineAbstract Background Acute myocardial infarction (AMI) is a leading cause of mortality, characterized by myocardial ischemia that induces cardiomyocyte apoptosis and subsequent cardiac dysfunction. Sirtuin 1 (Sirt1) has emerged as a key regulator of cell survival and apoptosis, particularly under hypoxic conditions. Methods An AMI animal model was established via ligation of the left anterior descending (LAD) coronary artery. Gene expression in the infarcted region was evaluated at various time points. Sirt1 overexpression and control lentivirus were administered to the peri-infarct region of mice heart. After LAD ligation, assessment on myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were performed. In vitro, primary mouse cardiomyocytes subjected to hypoxia were analyzed for gene expression, while interactions among Sirt1, Phd3, and Hif-1α were explored using diverse treatment approaches. Results A significant reduction in Sirt1 and Phd3 expression, along with an increase in Hif-1α and cleaved caspase-3, was observed in a time-dependent manner post-myocardial infarction (MI). In vitro findings revealed that hypoxia decreased nuclear Sirt1 and cytoplasmic Phd3 levels while promoting a time-dependent increase in Hif-1α and cleaved caspase-3. Furthermore, Sirt1 overexpression enhanced Phd3 expression in cardiomyocytes, suppressed Hif-1α and cleaved caspase-3 levels, and alleviated hypoxia-induced cardiomyocyte apoptosis. Notably, knockdown of Phd3 negated Sirt1’s inhibitory effect on Hif-1α, whereas Hif-1α knockdown promoted Sirt1 expression. Sirt1 overexpression reduced infarct size, decreased cardiomyocyte apoptosis, and improved cardiac function. Conclusions Sirt1 effectively reduces cardiomyocyte apoptosis and myocardial infarction size while enhancing cardiac function post-MI, primarily through the Phd3/Hif-1α signaling pathway.https://doi.org/10.1186/s10020-025-01155-zAcute myocardial infarctionApoptosisHypoxiaSirt1Phd3Hif-1α |
| spellingShingle | Yafen Chen Shuyao Shan Qiqi Xue Yan Ren Qihong Wu Jiawei Chen Ke Yang Jiumei Cao Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α Molecular Medicine Acute myocardial infarction Apoptosis Hypoxia Sirt1 Phd3 Hif-1α |
| title | Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α |
| title_full | Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α |
| title_fullStr | Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α |
| title_full_unstemmed | Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α |
| title_short | Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α |
| title_sort | sirtuin1 mitigates hypoxia induced cardiomyocyte apoptosis in myocardial infarction via phd3 hif 1α |
| topic | Acute myocardial infarction Apoptosis Hypoxia Sirt1 Phd3 Hif-1α |
| url | https://doi.org/10.1186/s10020-025-01155-z |
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