Embryonic Stem Cell‐Derived Exosomes Inhibit Doxorubicin‐Induced Pyroptosis in Cardiac Cells

Abstract

Doxorubicin (Dox) is a potent antineoplastic drug used to treat various cancers. Unfortunately, Dox administration is limited due to induction of adverse cardiotoxicity (DIC), which is mediated through oxidative stress, ER stress, and inflammation. However, it is unknown whether Dox induces an inflammasomne‐mediated cell death, called “pyroptosis” in heart. Pyroptosis occurs via activation of TLR‐4 receptor and generation of NLRP3 inflammasome in response to damage‐associated pattern molecules (DAPMs). This would follow‐up with stimulation of caspase‐1 cascade and secretion of pro‐inflammatory cytokines from the dead cells. This study is undertaken to determine whether Dox generates pyroptosis in cardiac cell culture model. Furthermore, to elucidate the protective effects of embryonic stem cell‐derived exosomes (ES‐Exos) in inhibiting pyroptotic cell death. For this purpose, we designed a cell culture model using H9c2 cadiomyoblasts. To generate DIC, H9c2 were exposed to Dox (2 μM for 24 hrs) to induce pyroptosis and accordingly treated with exosomes (10 μg for additional 24 hrs). Cells were assigned into 4 groups: Control, Dox, Dox+ES‐Exos, and Dox+MEF‐Exos (as negative control). According to western blot analysis, immunohistochemical staining and ELISA data, Dox administration caused significant increase in expression of inflammasome markers, TLR‐4 and NLRP3, (p<0.05), pyroptotic markers, caspase‐1, IL1‐β, Caspase‐11, and gasdermin‐D, (p<0.05), as well as pro‐inflammatory cytokines, TNF‐α and IL‐6, (p<0.05) in H9c2 cells. Conversely, increased pyroptosis and inflammation post‐Dox treatment were attenuated significantly upon ES‐Exos treatment in H9c2 cells (p<0.05). However, MEF‐Exos treatment did not make significant changes vs Dox group (non‐significant vs Dox). Overall, our data shows Dox induces pyroptosis and inflammation within cardiac cells, which can be inhibited following treatment with ES‐exosomes. The significance of this study is a new mechanistic insight on the pathophysiological role of NLRP3 inflammasome‐mediated pyroptosis in Dox‐induced cardiotoxicity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Exosomal miR-27b-3p Derived from Hypoxic Cardiac Microvascular Endothelial Cells Alleviates Rat Myocardial Ischemia/Reperfusion Injury through Inhibiting Oxidative Stress-Induced Pyroptosis via Foxo1/GSDMD Signaling

“…Exosomes contain RNA, lipids, and proteins and deliver signals to target cells, which is essential for intercellular communication and exchange of genetic information [ 17 ]. Exosomes derived from stem cells could inhibit inflammation and doxorubicin-induced pyroptosis in cardiac cells [ 11 , 18 , 19 ]. Dargani et al [ 18 ] indicated that doxorubicin promotes the expression of IL-1 β and IL-18 in exosomes derived from embryonic stem cells.…”

“…Exosomes derived from stem cells could inhibit inflammation and doxorubicin-induced pyroptosis in cardiac cells [11,18,19]. Dargani et al [18] indicated that doxorubicin promotes the expression of IL-1β and IL-18 in exosomes derived from embryonic stem cells. Evidence showed that the abundance of exosomal proteins, mRNA, and miRNA and exosomal therapeutic potential could be enhanced by hypoxia [20][21][22][23].…”