The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury
Available evidence indicates that neuregulin-1 (NRG-1) can provide a protection against myocardial ischemia/reperfusion (I/R) injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to...
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Elsevier
2025-03-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000242 |
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| author | Xin-Tao Li Xin-Yue Li Tian Tian Wen-He Yang Shuai-Guo Lyv Yi Cheng Kai Su Xi-Hua Lu Mu Jin Fu-Shan Xue |
| author_facet | Xin-Tao Li Xin-Yue Li Tian Tian Wen-He Yang Shuai-Guo Lyv Yi Cheng Kai Su Xi-Hua Lu Mu Jin Fu-Shan Xue |
| author_sort | Xin-Tao Li |
| collection | DOAJ |
| description | Available evidence indicates that neuregulin-1 (NRG-1) can provide a protection against myocardial ischemia/reperfusion (I/R) injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to be clarified. In this study, both an in vivo myocardial I/R injury model of rats and an in vitro hypoxia/reoxygenation (H/R) model of H9C2 cardiomyocytes were applied to determine whether NRG-1 postconditioning attenuated myocardial I/R injury through the regulation of mitophagy and to explore the underlying mechanisms. In the in vivo experiment, cardioprotective effects of NRG-1 were determined by infarct size, cardiac enzyme and histopathologic examinations. The potential downstream signaling pathways and molecular targets of NRG-1 were screened by the RNA sequencing and the Protein-Protein Interaction Networks. The expression levels of mitochondrial uncoupling protein 2 (UCP2) and mitophagy-related proteins in both the I/R myocardium and H/R cardiomyocytes were measured by immunofluorescence staining and Western blots. The activation of mitophagy was observed with transmission electron microscopy and JC-1 staining. The KEGG and GSEA analyses showed that the mitophagy-related signaling pathways were enriched in the I/R myocardium treated with NRG-1, and UCP2 exhibited a significant correlation between mitophagy and interaction with PINK1. Meanwhile, the treatment with mitophagy inhibitor Mdivi-1 significant eliminated the cardioprotective effects of NRG-1 postconditioning in vivo, and the challenge with UCP2 inhibitor genipin could also attenuate the activating effect of NRG-1 postconditioning on mitophagy. Consistently, the in vitro experiment using H9C2 cardiomyocytes showd that NRG-1 treatment significantly up-regulated the expression levels of UCP2 and mitophagy-related proteins, and activated the mitophagy, whereas the challenge with small interfering RNA-mediated UCP2 knockdown abolished the effects of NRG-1. Thus, it is conclused that NRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway. |
| format | Article |
| id | doaj-art-71f50a675fe84889b0fcd6d3f0cca0c2 |
| institution | DOAJ |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-71f50a675fe84889b0fcd6d3f0cca0c22025-08-20T03:11:54ZengElsevierRedox Biology2213-23172025-03-018010351110.1016/j.redox.2025.103511The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injuryXin-Tao Li0Xin-Yue Li1Tian Tian2Wen-He Yang3Shuai-Guo Lyv4Yi Cheng5Kai Su6Xi-Hua Lu7Mu Jin8Fu-Shan Xue9Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, ChinaDepartment of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, ChinaDepartment of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; Corresponding author.Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; Corresponding author.Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China; Corresponding author. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.Available evidence indicates that neuregulin-1 (NRG-1) can provide a protection against myocardial ischemia/reperfusion (I/R) injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to be clarified. In this study, both an in vivo myocardial I/R injury model of rats and an in vitro hypoxia/reoxygenation (H/R) model of H9C2 cardiomyocytes were applied to determine whether NRG-1 postconditioning attenuated myocardial I/R injury through the regulation of mitophagy and to explore the underlying mechanisms. In the in vivo experiment, cardioprotective effects of NRG-1 were determined by infarct size, cardiac enzyme and histopathologic examinations. The potential downstream signaling pathways and molecular targets of NRG-1 were screened by the RNA sequencing and the Protein-Protein Interaction Networks. The expression levels of mitochondrial uncoupling protein 2 (UCP2) and mitophagy-related proteins in both the I/R myocardium and H/R cardiomyocytes were measured by immunofluorescence staining and Western blots. The activation of mitophagy was observed with transmission electron microscopy and JC-1 staining. The KEGG and GSEA analyses showed that the mitophagy-related signaling pathways were enriched in the I/R myocardium treated with NRG-1, and UCP2 exhibited a significant correlation between mitophagy and interaction with PINK1. Meanwhile, the treatment with mitophagy inhibitor Mdivi-1 significant eliminated the cardioprotective effects of NRG-1 postconditioning in vivo, and the challenge with UCP2 inhibitor genipin could also attenuate the activating effect of NRG-1 postconditioning on mitophagy. Consistently, the in vitro experiment using H9C2 cardiomyocytes showd that NRG-1 treatment significantly up-regulated the expression levels of UCP2 and mitophagy-related proteins, and activated the mitophagy, whereas the challenge with small interfering RNA-mediated UCP2 knockdown abolished the effects of NRG-1. Thus, it is conclused that NRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway.http://www.sciencedirect.com/science/article/pii/S2213231725000242Ischemia/reperfusion injuryNeuregulin-1MitophagyUncoupling protein 2 |
| spellingShingle | Xin-Tao Li Xin-Yue Li Tian Tian Wen-He Yang Shuai-Guo Lyv Yi Cheng Kai Su Xi-Hua Lu Mu Jin Fu-Shan Xue The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury Redox Biology Ischemia/reperfusion injury Neuregulin-1 Mitophagy Uncoupling protein 2 |
| title | The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury |
| title_full | The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury |
| title_fullStr | The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury |
| title_full_unstemmed | The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury |
| title_short | The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury |
| title_sort | ucp2 pink1 lc3b mediated mitophagy is involved in the protection of nrg1 against myocardial ischemia reperfusion injury |
| topic | Ischemia/reperfusion injury Neuregulin-1 Mitophagy Uncoupling protein 2 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000242 |
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