Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway
Abstract Background The protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP). Methods We used a myocardial reperfusion injury rat m...
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| Format: | Article |
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BMC
2018-07-01
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| Series: | Molecular Medicine |
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| Online Access: | http://link.springer.com/article/10.1186/s10020-018-0040-7 |
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| author | Fuhua Wang Huan Wang Xuejing Liu Haiyi Yu Bo Zuo Zhu Song Ning Wang Wei Huang Guisong Wang |
| author_facet | Fuhua Wang Huan Wang Xuejing Liu Haiyi Yu Bo Zuo Zhu Song Ning Wang Wei Huang Guisong Wang |
| author_sort | Fuhua Wang |
| collection | DOAJ |
| description | Abstract Background The protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP). Methods We used a myocardial reperfusion injury rat model in vivo to compare the cardioprotective effects of NRG-1(3 μg/kg, iv. at the onset of reperfusion) and IP. In Langendorff isolated heart perfusion experiments, we used the erythroblastic leukaemia viral oncogene homolog 4 (ErbB4) inhibitor AG1478, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a mitogen-activated protein/extracellular signal regulated kinase (MEK) inhibitor PD98059 to clarify whether the protective effects of NRG-1and IP depend on the NRG-1/ErbB4 signals and the reperfusion injury salvage kinase (RISK) pathway. Infarct size was detected by Evans blue and TTC. Apoptosis was detected by TUNEL assays. The expression of NRG-1/ErbB4 and downstream ERK1/2, AKT, AMPK and p70s6K were detected by western blotting. Hematoxylin/eosin (H&E) staining was used for histological analysis. Results We found that NRG-1 and IP had similar effects on reducing myocardial infarct size and apoptosis in vivo. NRG-1 heart protein levels were upregulated in the IP group. Phosphorylation of AKT, ERK1/2 and ErbB4 were also increased in both the IP and NRG-1 groups. Furthermore, in Langendorff analyses, the ErbB4 inhibitor AG1478 suppressed the phosphorylation of ErbB4 and the RISK pathway and aggravated myocardial edema and fiber fracture, thereby inhibited the cardioprotective effects in both the IP and NRG-1 groups. For assessment of downstream signals, the PI3K inhibitor LY294002 and the MEK inhibitor PD98059 suppressed the phosphorylation of AKT and ERK1/2 respectively and abolished the cardioprotective effects induced by IP and NRG-1. Conclusion In conclusion, both IP and NRG-1 could reduce infarct size and apoptosis through ErbB4-dependent activation of the RISK pathway in the same model; these results indicated the therapeutic potential of NRG-1 as a pharmacological postconditioning agent against myocardial reperfusion injury. |
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| issn | 1076-1551 1528-3658 |
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| spelling | doaj.art-9e1b6cc7522c49dd894b98ebc049ce2e2022-12-21T22:40:36ZengBMCMolecular Medicine1076-15511528-36582018-07-0124111210.1186/s10020-018-0040-7Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathwayFuhua Wang0Huan Wang1Xuejing Liu2Haiyi Yu3Bo Zuo4Zhu Song5Ning Wang6Wei Huang7Guisong Wang8Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education. Beijing Key Laboratory of Cardiovascular Receptors ResearchInstitute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science CenterInstitute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science CenterDepartment of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education. Beijing Key Laboratory of Cardiovascular Receptors ResearchDepartment of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education. Beijing Key Laboratory of Cardiovascular Receptors ResearchDepartment of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education. Beijing Key Laboratory of Cardiovascular Receptors ResearchDepartment of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education. Beijing Key Laboratory of Cardiovascular Receptors ResearchInstitute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science CenterDepartment of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education. Beijing Key Laboratory of Cardiovascular Receptors ResearchAbstract Background The protective effect of Neuregulin-1 (NRG-1) on heart failure is well established. In this study, we assessed whether NRG-1 could protect the heart by mimicking the cardioprotective effects of ischaemic postconditioning (IP). Methods We used a myocardial reperfusion injury rat model in vivo to compare the cardioprotective effects of NRG-1(3 μg/kg, iv. at the onset of reperfusion) and IP. In Langendorff isolated heart perfusion experiments, we used the erythroblastic leukaemia viral oncogene homolog 4 (ErbB4) inhibitor AG1478, a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a mitogen-activated protein/extracellular signal regulated kinase (MEK) inhibitor PD98059 to clarify whether the protective effects of NRG-1and IP depend on the NRG-1/ErbB4 signals and the reperfusion injury salvage kinase (RISK) pathway. Infarct size was detected by Evans blue and TTC. Apoptosis was detected by TUNEL assays. The expression of NRG-1/ErbB4 and downstream ERK1/2, AKT, AMPK and p70s6K were detected by western blotting. Hematoxylin/eosin (H&E) staining was used for histological analysis. Results We found that NRG-1 and IP had similar effects on reducing myocardial infarct size and apoptosis in vivo. NRG-1 heart protein levels were upregulated in the IP group. Phosphorylation of AKT, ERK1/2 and ErbB4 were also increased in both the IP and NRG-1 groups. Furthermore, in Langendorff analyses, the ErbB4 inhibitor AG1478 suppressed the phosphorylation of ErbB4 and the RISK pathway and aggravated myocardial edema and fiber fracture, thereby inhibited the cardioprotective effects in both the IP and NRG-1 groups. For assessment of downstream signals, the PI3K inhibitor LY294002 and the MEK inhibitor PD98059 suppressed the phosphorylation of AKT and ERK1/2 respectively and abolished the cardioprotective effects induced by IP and NRG-1. Conclusion In conclusion, both IP and NRG-1 could reduce infarct size and apoptosis through ErbB4-dependent activation of the RISK pathway in the same model; these results indicated the therapeutic potential of NRG-1 as a pharmacological postconditioning agent against myocardial reperfusion injury.http://link.springer.com/article/10.1186/s10020-018-0040-7Neuregulin-1Pharmacological postconditioningIschaemic postconditioningMyocardial reperfusion injuryErbB4 |
| spellingShingle | Fuhua Wang Huan Wang Xuejing Liu Haiyi Yu Bo Zuo Zhu Song Ning Wang Wei Huang Guisong Wang Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway Molecular Medicine Neuregulin-1 Pharmacological postconditioning Ischaemic postconditioning Myocardial reperfusion injury ErbB4 |
| title | Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway |
| title_full | Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway |
| title_fullStr | Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway |
| title_full_unstemmed | Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway |
| title_short | Pharmacological postconditioning with Neuregulin-1 mimics the cardioprotective effects of ischaemic postconditioning via ErbB4-dependent activation of reperfusion injury salvage kinase pathway |
| title_sort | pharmacological postconditioning with neuregulin 1 mimics the cardioprotective effects of ischaemic postconditioning via erbb4 dependent activation of reperfusion injury salvage kinase pathway |
| topic | Neuregulin-1 Pharmacological postconditioning Ischaemic postconditioning Myocardial reperfusion injury ErbB4 |
| url | http://link.springer.com/article/10.1186/s10020-018-0040-7 |
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