Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages
Doxorubicin (DOXO)-induced cardiomyopathy (DIC) is a lethal complication in cancer patients. Major mechanisms of DIC involve oxidative stress in cardiomyocytes and hyperactivated immune response. Extracellular vesicles (EVs) mediate cell–cell communication during oxidative stress. However, functions...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/13465 |
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| author | Chontida Yarana Panjaree Siwaponanan Chayodom Maneechote Thawatchai Khuanjing Benjamin Ongnok Nanthip Prathumsap Siriporn C. Chattipakorn Nipon Chattipakorn Kovit Pattanapanyasat |
| author_facet | Chontida Yarana Panjaree Siwaponanan Chayodom Maneechote Thawatchai Khuanjing Benjamin Ongnok Nanthip Prathumsap Siriporn C. Chattipakorn Nipon Chattipakorn Kovit Pattanapanyasat |
| author_sort | Chontida Yarana |
| collection | DOAJ |
| description | Doxorubicin (DOXO)-induced cardiomyopathy (DIC) is a lethal complication in cancer patients. Major mechanisms of DIC involve oxidative stress in cardiomyocytes and hyperactivated immune response. Extracellular vesicles (EVs) mediate cell–cell communication during oxidative stress. However, functions of circulating EVs released after chronic DOXO exposure on cardiomyocytes and immune cells are still obscured. Herein, we developed a DIC in vivo model using male Wistar rats injected with 3 mg/kg DOXO for 6 doses within 30 days (18 mg/kg cumulative dose). One month after the last injection, the rats developed cardiotoxicity evidenced by increased BCL2-associated X protein and cleaved caspase-3 in heart tissues, along with N-terminal pro B-type natriuretic peptide in sera. Serum EVs were isolated by size exclusion chromatography. EV functions on H9c2 cardiomyocytes and NR8383 macrophages were evaluated. EVs from DOXO-treated rats (DOXO_EVs) attenuated ROS production via increased glutathione peroxidase-1 and catalase gene expression, and reduced hydrogen peroxide-induced cell death in cardiomyocytes. In contrast, DOXO_EVs induced ROS production, interleukin-6, and tumor necrosis factor-alpha, while suppressing arginase-1 gene expression in macrophages. These results suggested the pleiotropic roles of EVs against DIC, which highlight the potential role of EV-based therapy for DIC with a concern of its adverse effect on immune response. |
| first_indexed | 2024-03-09T19:00:05Z |
| format | Article |
| id | doaj.art-de20801a00434b6c91b9f364849696be |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:00:05Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-de20801a00434b6c91b9f364849696be2023-11-24T05:08:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123211346510.3390/ijms232113465Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in MacrophagesChontida Yarana0Panjaree Siwaponanan1Chayodom Maneechote2Thawatchai Khuanjing3Benjamin Ongnok4Nanthip Prathumsap5Siriporn C. Chattipakorn6Nipon Chattipakorn7Kovit Pattanapanyasat8Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, 999 Phuttamonthon 4 Road, Salaya, Nakhon Pathom 73170, ThailandCenter of Excellence for Microparticle and Exosome in Diseases, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ThailandCardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandCardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandCardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandCardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandCardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandCardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ThailandCenter of Excellence for Microparticle and Exosome in Diseases, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ThailandDoxorubicin (DOXO)-induced cardiomyopathy (DIC) is a lethal complication in cancer patients. Major mechanisms of DIC involve oxidative stress in cardiomyocytes and hyperactivated immune response. Extracellular vesicles (EVs) mediate cell–cell communication during oxidative stress. However, functions of circulating EVs released after chronic DOXO exposure on cardiomyocytes and immune cells are still obscured. Herein, we developed a DIC in vivo model using male Wistar rats injected with 3 mg/kg DOXO for 6 doses within 30 days (18 mg/kg cumulative dose). One month after the last injection, the rats developed cardiotoxicity evidenced by increased BCL2-associated X protein and cleaved caspase-3 in heart tissues, along with N-terminal pro B-type natriuretic peptide in sera. Serum EVs were isolated by size exclusion chromatography. EV functions on H9c2 cardiomyocytes and NR8383 macrophages were evaluated. EVs from DOXO-treated rats (DOXO_EVs) attenuated ROS production via increased glutathione peroxidase-1 and catalase gene expression, and reduced hydrogen peroxide-induced cell death in cardiomyocytes. In contrast, DOXO_EVs induced ROS production, interleukin-6, and tumor necrosis factor-alpha, while suppressing arginase-1 gene expression in macrophages. These results suggested the pleiotropic roles of EVs against DIC, which highlight the potential role of EV-based therapy for DIC with a concern of its adverse effect on immune response.https://www.mdpi.com/1422-0067/23/21/13465doxorubicincardiotoxicityextracellular vesicleoxidative stressmacrophage |
| spellingShingle | Chontida Yarana Panjaree Siwaponanan Chayodom Maneechote Thawatchai Khuanjing Benjamin Ongnok Nanthip Prathumsap Siriporn C. Chattipakorn Nipon Chattipakorn Kovit Pattanapanyasat Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages International Journal of Molecular Sciences doxorubicin cardiotoxicity extracellular vesicle oxidative stress macrophage |
| title | Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages |
| title_full | Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages |
| title_fullStr | Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages |
| title_full_unstemmed | Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages |
| title_short | Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages |
| title_sort | extracellular vesicles released after doxorubicin treatment in rats protect cardiomyocytes from oxidative damage and induce pro inflammatory gene expression in macrophages |
| topic | doxorubicin cardiotoxicity extracellular vesicle oxidative stress macrophage |
| url | https://www.mdpi.com/1422-0067/23/21/13465 |
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