Human trophoblast-derived exosomes attenuate doxorubicin-induced cardiac injury by regulating miR-200b and downstream Ze
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Journal of Nanobiotechnology Open Access
RESEARCH
Human trophoblast‑derived exosomes attenuate doxorubicin‑induced cardiac injury by regulating miR‑200b and downstream Zeb1 Jie Ni1†, Yihai Liu1†, Lina Kang2, Lian Wang2, Zhonglin Han2, Kun Wang2*, Biao Xu1,2* and Rong Gu2*
Abstract Human trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in heart failure. However, whether trophoblast stem cell-derived exosomes (TSC-Exos) can protect cardiomyocytes from doxorubicin (Dox)induced injury remains unclear. In the present study, TSC-Exos were isolated from the supernatants of human trophoblasts using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. In vitro, primary cardiomyocytes were subjected to Dox and treated with TSC-Exos, miR-200b mimic or miR200b inhibitor. Cellular apoptosis was observed by flow cytometry and immunoblotting. In vivo, mice were intraperitoneally injected into Dox to establish a heart failure model. Then, different groups of mice were administered either PBS, adeno-associated virus (AAV)-vector, AAV-miR-200b-inhibitor or TSC-Exos via tail vein injection. Then, the cardiac function, cardiac fibrosis and cardiomyocyte apoptosis in each group were evaluated, and the downstream molecular mechanism was explored. TSC-Exos and miR-200b inhibitor both decreased primary cardiomyocyte apoptosis. Similarly, mice receiving TSC-Exos and AAV-miR-200b inhibitor exhibited improved cardiac function, accompanied by reduced apoptosis and inflammation. The bioinformatic prediction and luciferase reporter results confirmed that Zeb1 was a downstream target of miR-200b and had an antiapoptotic effect. TSC-Exos attenuated doxorubicininduced cardiac injury by playing antiapoptotic and anti-inflammatory roles. The underlying mechanism could be an increase in Zeb1 expression by the inhibition of miR-200b expression. In summary, this study sheds new light on the application of TSC-Exos as a potential therapeutic tool for heart failure. Keywords: Trophoblasts, Exosomes, miR-200b, Heart failure Introduction Cancer mortality has decreased during recent decades due to the widespread use of anthracyclines [1]. However, the number of patients suffering from the longterm effects of cardiotoxicity has increased [2, 3]. Several *Correspondence: [email protected]; [email protected]; gurong. [email protected] † Jie Ni and Yihai Liu contributed equally to this work 1 Department of Cardiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210008, Jiangsu, People’s Republic of China 2 Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, Jiangsu, People’s Republic of China
agents used in cancer treatment, such as doxorubicin (Dox), can adversely affect cardiac function and lead to congestive heart failure, which is a leading cause of disability in long-term survivors of cancer [4, 5] and a growing problem in the field of cardio-oncology. Dox is an anthrac
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