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18 March 2020 : Animal Research  

The Effects of Inhibition of MicroRNA-375 in a Mouse Model of Doxorubicin-Induced Cardiac Toxicity

Hao Zhang1ABCDE, Yikui Tian1ABCE, Degang Liang1BCD, Qiang Fu1BCDE, Liqun Jia1BCD, Dawei Wu1BC, Xinyuan Zhu1ABCDEF*

DOI: 10.12659/MSM.920557

Med Sci Monit 2020; 26:e920557

Abstract

BACKGROUND: Doxorubicin-induced myocardial toxicity is associated with oxidative stress, cardiomyocyte, apoptosis, and loss of contractile function. Previous studies showed that microRNA-375 (miR-375) expression was increased in mouse models of heart failure and clinically, and that inhibition of miR-375 reduced inflammation and increased survival of cardiomyocytes. This study aimed to investigate the effects and mechanisms of inhibition of miR-375 in a mouse model of doxorubicin-induced cardiac toxicity in vivo and in doxorubicin-treated rat and mouse cardiomyocytes in vitro.

MATERIAL AND METHODS: The mouse model of doxorubicin-induced cardiac toxicity was developed using an intraperitoneal injection of doxorubicin (15 mg/kg diluted in 0.9% saline) for eight days. Treatment was followed by a single subcutaneous injection of miR-375 inhibitor. H9c2 rat cardiac myocytes and adult murine cardiomyocytes (AMCs) were cultured in vitro and treated with doxorubicin, with and without pretreatment with miR-375 inhibitor.

RESULTS: Doxorubicin significantly upregulated miR-375 expression in vitro and in vivo, and inhibition of miR-375 re-established myocardial redox homeostasis, prevented doxorubicin-induced oxidative stress and cardiomyocyte apoptosis, and activated the PDK1/AKT axis by reducing the direct binding of miR-375 to 3’ UTR of the PDK1 gene. Inhibition of PDK1 and AKT abolished the protective role of miR-375 inhibition on doxorubicin-induced oxidative damage.

CONCLUSIONS: Inhibition of miR-375 prevented oxidative damage in a mouse model of doxorubicin-induced cardiac toxicity in vivo and in doxorubicin-treated rat and mouse cardiomyocytes in vitro through the PDK1/AKT signaling pathway.

Keywords: Doxorubicin, cardiotoxicity, Cells, Cultured, Mice, Inbred C57BL, Myocytes, Cardiac

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750