LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis
Regulated necrosis (necroptosis) and apoptosis are important biological features of ischemia-reperfusion (I/R) injury. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) has been reported to play impo...
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Elsevier
2024-12-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724003781 |
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| author | Mengmeng Zhao Zihui Zheng Jianfang Liu Yao Xu Jishou Zhang Shanshan Peng Juan-Juan Qin Jun Wan Menglong Wang |
| author_facet | Mengmeng Zhao Zihui Zheng Jianfang Liu Yao Xu Jishou Zhang Shanshan Peng Juan-Juan Qin Jun Wan Menglong Wang |
| author_sort | Mengmeng Zhao |
| collection | DOAJ |
| description | Regulated necrosis (necroptosis) and apoptosis are important biological features of ischemia-reperfusion (I/R) injury. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) has been reported to play important roles in various cardiovascular disease. In this study, we aimed to determine whether LGR6 suppresses I/R-induced myocardial necroptosis and the underlying molecular mechanisms. We generated LGR6 knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of LGR6 and its downstream molecules were subsequently identified using RNA sequencing and CHIP assays. We observed significantly downregulated LGR6 expression in hearts post myocardial I/R and cardiomyocytes post hypoxia and reoxygenation (HR). LGR6 deficiency promoted and LGR6 overexpression inhibited necroptosis and acute myocardial injury after I/R. Mechanistically, in vivo and in vitro experiments suggest that LGR6 regulates the expression of STAT2 and ZBP1 by activating the Wnt signaling pathway, thereby inhibiting cardiomyocyte necroptosis after HR. Inhibiting STAT2 and ZBP1 effectively alleviated the aggravating effect of LGR6 deficiency on myocardial necroptosis after I/R. Furthermore, activating LGR6 with RSPO3 also effectively protected mice from acute myocardial I/R injury. Our findings reveal that RSPO3-LGR6 axis downregulates the expression of STAT2 and ZBP1 through the Wnt signaling pathway, thereby inhibiting I/R-induced myocardial injury and necroptosis. Targeting the RSPO3-LGR6 axis may be a potential therapeutic strategy to treat myocardial I/R injury. |
| format | Article |
| id | doaj-art-9b9081dbe8e4480683d45a8aac8038d5 |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-9b9081dbe8e4480683d45a8aac8038d52024-12-08T06:09:56ZengElsevierRedox Biology2213-23172024-12-0178103400LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosisMengmeng Zhao0Zihui Zheng1Jianfang Liu2Yao Xu3Jishou Zhang4Shanshan Peng5Juan-Juan Qin6Jun Wan7Menglong Wang8Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, ChinaDepartment of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China; Center for Healthy Aging, Wuhan University School of Nursing, Wuhan, China; Corresponding author. Department of Geriatrics, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430060, China.Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China; Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.Regulated necrosis (necroptosis) and apoptosis are important biological features of ischemia-reperfusion (I/R) injury. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) has been reported to play important roles in various cardiovascular disease. In this study, we aimed to determine whether LGR6 suppresses I/R-induced myocardial necroptosis and the underlying molecular mechanisms. We generated LGR6 knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of LGR6 and its downstream molecules were subsequently identified using RNA sequencing and CHIP assays. We observed significantly downregulated LGR6 expression in hearts post myocardial I/R and cardiomyocytes post hypoxia and reoxygenation (HR). LGR6 deficiency promoted and LGR6 overexpression inhibited necroptosis and acute myocardial injury after I/R. Mechanistically, in vivo and in vitro experiments suggest that LGR6 regulates the expression of STAT2 and ZBP1 by activating the Wnt signaling pathway, thereby inhibiting cardiomyocyte necroptosis after HR. Inhibiting STAT2 and ZBP1 effectively alleviated the aggravating effect of LGR6 deficiency on myocardial necroptosis after I/R. Furthermore, activating LGR6 with RSPO3 also effectively protected mice from acute myocardial I/R injury. Our findings reveal that RSPO3-LGR6 axis downregulates the expression of STAT2 and ZBP1 through the Wnt signaling pathway, thereby inhibiting I/R-induced myocardial injury and necroptosis. Targeting the RSPO3-LGR6 axis may be a potential therapeutic strategy to treat myocardial I/R injury.http://www.sciencedirect.com/science/article/pii/S2213231724003781LGR6NecroptosisZBP1STAT2Myocardial ischemia-reperfusion injury |
| spellingShingle | Mengmeng Zhao Zihui Zheng Jianfang Liu Yao Xu Jishou Zhang Shanshan Peng Juan-Juan Qin Jun Wan Menglong Wang LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis Redox Biology LGR6 Necroptosis ZBP1 STAT2 Myocardial ischemia-reperfusion injury |
| title | LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis |
| title_full | LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis |
| title_fullStr | LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis |
| title_full_unstemmed | LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis |
| title_short | LGR6 protects against myocardial ischemia-reperfusion injury via suppressing necroptosis |
| title_sort | lgr6 protects against myocardial ischemia reperfusion injury via suppressing necroptosis |
| topic | LGR6 Necroptosis ZBP1 STAT2 Myocardial ischemia-reperfusion injury |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724003781 |
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