{"title":"Neuregulin-1 通过上调 YAP 来抑制衰老,从而降低多柔比星诱导的心脏毒性","authors":"","doi":"10.1016/j.intimp.2024.113278","DOIUrl":null,"url":null,"abstract":"<div><div>The cardiotoxicity of Doxorubicin (Dox) limits its clinical application, creating an urgent need to investigate its underlying mechanism and develop effective therapies. Senescence plays an important role in Dox-induced cardiotoxicity (DIC). Recently, Neuregulin-1 (NRG1) was found to regulate Yes-associated protein (YAP), which was reported to inhibit senescence, suggesting that NRG1 might be used to treat DIC by inhibiting senescence through YAP regulation. We examined the changes and regulatory roles of YAP and senescence in Dox cardiotoxicity and whether NRG1 could reduce DIC in chronic DIC mice and Dox-treated H9c2 cells. Our study revealed that sustained small doses of Dox impaired cardiac function and H9c2 cell viability, induced myocardial senescence, and inhibited YAP expression. Conversely, high levels of YAP inhibited Dox-induced senescence in H9c2 cells, indicating that Dox promotes myocardial senescence by inhibiting YAP. In addition, we found that exogenous NRG1 inhibited the phosphorylation of LATS1 and MST1, thereby inhibiting YAP phosphorylation and promote the nuclear translocation of YAP, inhibiting senescence and attenuating Dox-induced cardiotoxicity. YAP knockdown or inhibition of YAP binding to TEA domain transcription factor protein (TEAD)blocks the protective effects of NRG1. In conclusion, our study suggests that Dox-induced myocardial senescence through YAP inhibition is one of the pathological mechanisms of its cardiotoxicity. Additionally, NRG1 reduces DIC by upregulating YAP to inhibit senescence.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Neuregulin-1 reduces Doxorubicin-induced cardiotoxicity by upregulating YAP to inhibit senescence\",\"authors\":\"\",\"doi\":\"10.1016/j.intimp.2024.113278\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The cardiotoxicity of Doxorubicin (Dox) limits its clinical application, creating an urgent need to investigate its underlying mechanism and develop effective therapies. Senescence plays an important role in Dox-induced cardiotoxicity (DIC). Recently, Neuregulin-1 (NRG1) was found to regulate Yes-associated protein (YAP), which was reported to inhibit senescence, suggesting that NRG1 might be used to treat DIC by inhibiting senescence through YAP regulation. We examined the changes and regulatory roles of YAP and senescence in Dox cardiotoxicity and whether NRG1 could reduce DIC in chronic DIC mice and Dox-treated H9c2 cells. Our study revealed that sustained small doses of Dox impaired cardiac function and H9c2 cell viability, induced myocardial senescence, and inhibited YAP expression. Conversely, high levels of YAP inhibited Dox-induced senescence in H9c2 cells, indicating that Dox promotes myocardial senescence by inhibiting YAP. In addition, we found that exogenous NRG1 inhibited the phosphorylation of LATS1 and MST1, thereby inhibiting YAP phosphorylation and promote the nuclear translocation of YAP, inhibiting senescence and attenuating Dox-induced cardiotoxicity. YAP knockdown or inhibition of YAP binding to TEA domain transcription factor protein (TEAD)blocks the protective effects of NRG1. In conclusion, our study suggests that Dox-induced myocardial senescence through YAP inhibition is one of the pathological mechanisms of its cardiotoxicity. Additionally, NRG1 reduces DIC by upregulating YAP to inhibit senescence.</div></div>\",\"PeriodicalId\":13859,\"journal\":{\"name\":\"International immunopharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-10-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International immunopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1567576924018009\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1567576924018009","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Neuregulin-1 reduces Doxorubicin-induced cardiotoxicity by upregulating YAP to inhibit senescence
The cardiotoxicity of Doxorubicin (Dox) limits its clinical application, creating an urgent need to investigate its underlying mechanism and develop effective therapies. Senescence plays an important role in Dox-induced cardiotoxicity (DIC). Recently, Neuregulin-1 (NRG1) was found to regulate Yes-associated protein (YAP), which was reported to inhibit senescence, suggesting that NRG1 might be used to treat DIC by inhibiting senescence through YAP regulation. We examined the changes and regulatory roles of YAP and senescence in Dox cardiotoxicity and whether NRG1 could reduce DIC in chronic DIC mice and Dox-treated H9c2 cells. Our study revealed that sustained small doses of Dox impaired cardiac function and H9c2 cell viability, induced myocardial senescence, and inhibited YAP expression. Conversely, high levels of YAP inhibited Dox-induced senescence in H9c2 cells, indicating that Dox promotes myocardial senescence by inhibiting YAP. In addition, we found that exogenous NRG1 inhibited the phosphorylation of LATS1 and MST1, thereby inhibiting YAP phosphorylation and promote the nuclear translocation of YAP, inhibiting senescence and attenuating Dox-induced cardiotoxicity. YAP knockdown or inhibition of YAP binding to TEA domain transcription factor protein (TEAD)blocks the protective effects of NRG1. In conclusion, our study suggests that Dox-induced myocardial senescence through YAP inhibition is one of the pathological mechanisms of its cardiotoxicity. Additionally, NRG1 reduces DIC by upregulating YAP to inhibit senescence.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.