Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages

• Published in: International journal of molecular sciences 2022-11, Vol.23 (21), p.13465
• Main Authors: Yarana, Chontida, Siwaponanan, Panjaree, Maneechote, Chayodom, Khuanjing, Thawatchai, Ongnok, Benjamin, Prathumsap, Nanthip, Chattipakorn, Siriporn C, Chattipakorn, Nipon, Pattanapanyasat, Kovit
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antioxidants; Apoptosis; Arginase; Brain natriuretic peptide; Cancer; Cardiomyocytes; Cardiomyopathies - chemically induced; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathy; Cardiotoxicity; Cardiovascular disease; Caspase-3; Catalase; Cell death; Chemotherapy; Doxorubicin; Doxorubicin - pharmacology; extracellular vesicle; Extracellular vesicles; Extracellular Vesicles - metabolism; Gene Expression; Glutathione peroxidase; Hydrogen peroxide; Immune response; Immune system; Inflammation; Interleukin 6; macrophage; Macrophages; Macrophages - metabolism; Male; Myocytes, Cardiac - metabolism; Oxidative Stress; Peroxidase; Proteins; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Size exclusion chromatography; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vesicles
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232113465

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.