14 March 2020 : Animal Research
MicroRNA-143 Increases Oxidative Stress and Myocardial Cell Apoptosis in a Mouse Model of Doxorubicin-Induced Cardiac ToxicityXin-Qiang Li1ABCDE, Ya-Kui Liu1AEF*, Jun Yi1BCDE, Jia-Shou Dong1CDE, Pan-Pan Zhang1BCD, Lei Wan1BCD, Kui Li1CD
Med Sci Monit 2020; 26:e920394
BACKGROUND: Oxidative stress and myocardial apoptosis are features of doxorubicin-induced cardiac toxicity that can result in cardiac dysfunction. Previous studies showed that microRNA-143 (miR-143) was expressed in the myocardium and had a role in cardiac function. This study aimed to investigate the effects and possible molecular mechanisms of miR-143 on oxidative stress and myocardial cell apoptosis in a mouse model of doxorubicin-induced cardiac toxicity.
MATERIAL AND METHODS: Mice underwent intraperitoneal injection of doxorubicin (15 mg/kg) daily for eight days to develop the mouse model of doxorubicin-induced cardiac toxicity. Four days before doxorubicin administration, a group of mice was pretreated daily with a miR-143 antagonist (25 mg/kg/day) for four consecutive days by tail vein injection. The study included the use of a miR-143 antagomir, or anti-microRNA, an oligonucleotide that silenced endogenous microRNA (miR), and an agomir to miR-143, and also the AKT inhibitor, MK2206. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblot analysis were used to measure mRNA and protein expression, respectively.
RESULTS: Doxorubicin treatment increased the expression of miR-143, which was reduced by the miR-143 antagomir. Overexpression of miR-143 increased doxorubicin-induced myocardial apoptosis and oxidative stress. The use of the miR-143 antagomir significantly activated protein kinase B (PKB) and AKT, which were reduced in the presence of the AKT inhibitor, MK2206. However, the use of the miR-143 antagomir further down-regulated AKT phosphorylation following doxorubicin treatment and increased AKT activation.
CONCLUSIONS: In a mouse model of doxorubicin-induced cardiac toxicity, miR-143 increased oxidative stress and myocardial cell apoptosis following doxorubicin treatment by inhibiting AKT.
Keywords: Doxorubicin, Antagomirs, cardiotoxicity, Cell Line, Heart, Heterocyclic Compounds, 3-Ring, Myocardium, Myocytes, Cardiac, Phosphorylation, Proto-Oncogene Proteins c-akt, Up-Regulation
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