Abstract
Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.
Highlights
Doxorubicin (DOX), a quinone-containing anthracycline, is effective in the treatment of severe leukemia and malignant lymphomas [1]
The study by Zhang et al showed that miR-152 was closely involved in the antiapoptotic effect of tanshinone IIA in cardiomyocytes [19]. miR-152 promoted the regeneration of the damaged neonatal heart through glycolysis [26]
For the first time, we demonstrated that DOX decreased miR-152 expression, and supplementation of miR-152 resulted in cardioprotection from DOX-induced cardiotoxicity in mice and cardiomyocytes
Summary
Doxorubicin (DOX), a quinone-containing anthracycline, is effective in the treatment of severe leukemia and malignant lymphomas [1]. The mechanism of DOX-induced cardiotoxicity was complex, but accumulating evidence indicated that oxidative stress and inflammation were closely involved [3, 4]. Available laboratory evidence showed that reactive oxygen species (ROS) and subsequent lipid peroxidation could be detected in the hearts within three hours after DOX treatment [5,6,7,8]. Nuclear factor kappa-B (NF-κB) activation by DOX was observed very early in the hearts of mice [9]. Accumulation of ROS and inflammation caused caspase-3 activation and resulted in myocardial apoptosis [10]. Inhibition of these alterations would be of great significance to the treatment of DOX-related cardiac toxicity
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