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 miR-200b 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 doxorubicin-induced 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.
Highlights
Cancer mortality has decreased during recent decades due to the widespread use of anthracyclines [1]
The Dox+AAV groups received a tail vein injection of 25 μl (1*10^11 v.g.) of adeno-associated virus serotype 9 (AAV9; GeneChem; Shanghai), which carried miR200b inhibitor, while the Dox+Vector groups received an equivalent dose of empty virus
Previous studies showed that Trophoblast stem cells (TSC) could decrease the expression of miR-200b in cardiac tissues [22]
Summary
Cancer mortality has decreased during recent decades due to the widespread use of anthracyclines [1]. The number of patients suffering from the longterm effects of cardiotoxicity has increased [2, 3]. Dox is an anthracycline cytostatic agent that has been in clinical use for almost a half century [6,7,8]. Cumulative doses of Dox were found to be harmful to the myocardium [9], leading to left ventricular dysfunction and the development of heart failure, namely, Doxinduced cardiotoxicity. The underlying mechanisms include mitochondrial iron accumulation and reactive oxygen species (ROS) burst [10,11,12,13], eventually leading to cell apoptosis or cell necrosis [14,15,16,17,18].
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