Abstract
Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its cardiotoxicity limits its clinical application. A better understanding of the molecular mechanisms underlying DOX cardiotoxicity will benefit clinical practice and remedy heart failure. Our present study observed that DOX caused cardiomyocyte (H9c2) apoptosis via the induction of abnormal mitochondrial fission. Notably, the expression levels of p21 increased in DOX-treated cardiomyocytes, and the silencing of p21 using siRNA greatly attenuated mitochondrial fission and apoptosis in cardiomyocytes. We also found that miR-499-5p could directly target p21 and attenuated DOX-induced mitochondrial fission and apoptosis. The role of the miR-499-5p-p21 axis in the prevention of DOX cardiotoxicity was also validated in the mice model. DOX treatment induced an upregulation of p21, which induced subsequent abnormal mitochondrial fission and myocardial apoptosis in mouse heart. Adenovirus-harboring miR-499-5p-overexpressing mice exhibited significantly reduced p21 expression, mitochondrial fission and myocardial apoptosis in hearts following DOX administration. The miR-499-5p-overexpressing mice also exhibited improved cardiomyocyte hypertrophy and cardiac function after DOX treatment. However, miR-499-5p was not involved in the DOX-induced apoptosis of cancer cells. Taken together, these findings reveal an emerging role of p21 in the regulation of mitochondrial fission program. miR-499-5p attenuated mitochondrial fission and DOX cardiotoxicity via the targeting of p21. These results provide new evidence for the miR-499-5p-p21 axis in the attenuation of DOX cardiotoxicity. The development of new therapeutic strategies based on the miR-499-5p-p21 axis is a promising path to overcome DOX cardiotoxicity as a chemotherapy for cancer treatment.
Highlights
Doxorubicin (DOX), known as adriamycin (ADR), exerts a killing effect on a variety of tumors, and it is a widely used anti-tumor drug (Levis et al, 2017)
We detected miR-499-5p expression levels in cardiomyocytes exposed to DOX to investigate the role of miR-499-5p in DOX-induced cardiotoxicity. miR-499-5p expression was significantly downregulated after DOX (2 μM) treatment (Figure 1A)
Knockdown of miR-499-5p sensitized cardiomyocytes to DOX, which induced mitochondrial fission and apoptosis in cardiomyocytes at a lower concentration (0.2 μM) (Figures 1F,H,K). These results suggest the involvement of miR-499-5p in DOX cardiotoxicity and an attenuation of DOX-induced apoptosis in cardiomyocytes via inhibition of mitochondrial fission by miR-499-5p
Summary
Doxorubicin (DOX), known as adriamycin (ADR), exerts a killing effect on a variety of tumors, and it is a widely used anti-tumor drug (Levis et al, 2017). A previous study found that DOX-induced cardiotoxicity primarily involved the production of reactive oxygen species (ROS) (Ichikawa et al, 2014), lipid peroxidation (Yarana et al, 2018), DNA damage (Li et al, 2009), mitochondrial dysfunction (Dhingra et al, 2014), apoptosis (Kumar et al, 2001), and autophagy dysregulation (Bartlett et al, 2017). These toxicities caused cell death of cardiomyocyte. A better understanding of the molecular mechanisms underlying DOX cardiotoxicity will improve the clinical application of DOX during cancer therapy (Kluza et al, 2004)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
