{"title":"Dehydroevodiamine Alleviates Doxorubicin-Induced Cardiomyocyte Injury by Regulating Neuregulin-1/ErbB Signaling","authors":"Song Jie, Guo Wenying, Sun Lebo","doi":"10.1155/cdr/5538740","DOIUrl":null,"url":null,"abstract":"<p><b>Background:</b> Doxorubicin (DOX) is a widely used antitumor drug; however, its use is limited by the risk of serious cardiotoxicity. Dehydroevodiamine (DHE) is a quinazoline alkaloid which has antiarrhythmic effects. The aim of this study was to investigate the protective effect of DHE on doxorubicin-induced cardiotoxicity (DIC) and its potential mechanism.</p><p><b>Materials and Methods:</b> Rat H9c2 cardiomyocytes were exposed to DOX for 24 h to establish a DOX-induced cardiomyocyte injury model. DHE and ErbB inhibitor AG1478 were used to treat H9c2 cells to investigate their effects. Cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays were used to evaluate cell viability. Flow cytometry and caspase-3 activity assay were used to detect apoptosis. Western blot was used to detect the expression levels of apoptosis-related proteins and neuregulin-1 (NRG1)/ErbB pathway–related proteins. The levels of proinflammatory cytokines and markers of oxidative stress were also detected, respectively. Quantitative polymerase chain reaction (qPCR) was used to detect mRNA expression levels of hub genes.</p><p><b>Results:</b> DHE enhanced cardiomyocyte viability and decreased LDH release in a concentration- and time-dependent manner. DHE also significantly inhibited DOX-induced cardiomyocyte apoptosis, inflammation, and oxidative stress. Bioinformatics analysis showed that the protective mechanism of DHE against DIC was related to ErbB signaling pathway. DOX treatment significantly reduced NRG1, p-ErbB2, and p-ErbB4 protein expression levels in cardiomyocytes, while DHE pretreatment reversed this effect. ErbB inhibitor AG1478 reversed the protective effect of DHE on cardiomyocytes.</p><p><b>Conclusion:</b> DHE protects cardiomyocytes against DOX by regulating NRG1/ErbB pathway. DHE may be a potential agent for the prevention and treatment of DIC.</p>","PeriodicalId":9582,"journal":{"name":"Cardiovascular Therapeutics","volume":"2024 1","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/cdr/5538740","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/cdr/5538740","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Doxorubicin (DOX) is a widely used antitumor drug; however, its use is limited by the risk of serious cardiotoxicity. Dehydroevodiamine (DHE) is a quinazoline alkaloid which has antiarrhythmic effects. The aim of this study was to investigate the protective effect of DHE on doxorubicin-induced cardiotoxicity (DIC) and its potential mechanism.
Materials and Methods: Rat H9c2 cardiomyocytes were exposed to DOX for 24 h to establish a DOX-induced cardiomyocyte injury model. DHE and ErbB inhibitor AG1478 were used to treat H9c2 cells to investigate their effects. Cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays were used to evaluate cell viability. Flow cytometry and caspase-3 activity assay were used to detect apoptosis. Western blot was used to detect the expression levels of apoptosis-related proteins and neuregulin-1 (NRG1)/ErbB pathway–related proteins. The levels of proinflammatory cytokines and markers of oxidative stress were also detected, respectively. Quantitative polymerase chain reaction (qPCR) was used to detect mRNA expression levels of hub genes.
Results: DHE enhanced cardiomyocyte viability and decreased LDH release in a concentration- and time-dependent manner. DHE also significantly inhibited DOX-induced cardiomyocyte apoptosis, inflammation, and oxidative stress. Bioinformatics analysis showed that the protective mechanism of DHE against DIC was related to ErbB signaling pathway. DOX treatment significantly reduced NRG1, p-ErbB2, and p-ErbB4 protein expression levels in cardiomyocytes, while DHE pretreatment reversed this effect. ErbB inhibitor AG1478 reversed the protective effect of DHE on cardiomyocytes.
Conclusion: DHE protects cardiomyocytes against DOX by regulating NRG1/ErbB pathway. DHE may be a potential agent for the prevention and treatment of DIC.
期刊介绍:
Cardiovascular Therapeutics (formerly Cardiovascular Drug Reviews) is a peer-reviewed, Open Access journal that publishes original research and review articles focusing on cardiovascular and clinical pharmacology, as well as clinical trials of new cardiovascular therapies. Articles on translational research, pharmacogenomics and personalized medicine, device, gene and cell therapies, and pharmacoepidemiology are also encouraged.
Subject areas include (but are by no means limited to):
Acute coronary syndrome
Arrhythmias
Atherosclerosis
Basic cardiac electrophysiology
Cardiac catheterization
Cardiac remodeling
Coagulation and thrombosis
Diabetic cardiovascular disease
Heart failure (systolic HF, HFrEF, diastolic HF, HFpEF)
Hyperlipidemia
Hypertension
Ischemic heart disease
Vascular biology
Ventricular assist devices
Molecular cardio-biology
Myocardial regeneration
Lipoprotein metabolism
Radial artery access
Percutaneous coronary intervention
Transcatheter aortic and mitral valve replacement.