MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2

Abstract

Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px. Total of 18 differentially expressed microRNAs in rat heart tissue caused by DOX were screened out using microRNA microarray assay, especially showing that miR-140-5p was significantly increased by DOX which was selected as the target miRNA. Double-luciferase reporter assay showed that miR-140-5p directly targeted Nrf2 and Sirt2, as a result of affecting the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a, and thereby increasing DOX-caused myocardial oxidative damage. In addition, the levels of intracellular ROS were significantly increased or decreased in H9C2 cells treated with DOX after miR-140-5p mimic or miR-140-5p inhibitor transfection, respectively, as well as the changed expression levels of Nrf2 and Sirt2. Furthermore, DOX- induced myocardial oxidative damage was worsened in mice treated with miR-140-5p agomir, and however the injury was alleviated in the mice administrated with miR-140-5p antagomir. Therefore, miR-140-5p plays an important role in DOX-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Our data provide novel insights for investigating DOX-induced heart injury. In addition, miR-140-5p/ Nrf2 and miR-140-5p/Sirt2 may be the new targets to treat DOX-induced cardiotoxicity.

FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

“…Previous studies indicated that Nrf2 deficiency exacerbated DOX-induced cardiotoxicity, whereas Nrf2 activation figure (a, b), *P < 0.05 versus the corresponding normal saline (NS) group mice injected with negative control (NC) adeno-associated virus 9, # P < 0.05 versus DOX-treated mice injected with AAV9-NC. In figure (c, d), *P < 0.05 versus PBS group treated with control vehicle, # P < 0.05 versus DOXtreated H9C2 cells with irisin protection provided protection against cardiac dysfunction in response to DOX [7,45]. Here, we found that irisin treatment blocked DOX-induced Nrf2 downregulation and preserved its transcriptional activity, as confirmed by the increased HO-1 protein level and Nqo1, Gclc, Gclm mRNA level (Fig.…”

“…Excessive ROS induces oxidative damage to biological macromolecules, including lipids, proteins and DNA, and disrupts cellular membrane integrity and function [6]. Moreover, DOX-evoked oxidative stress can directly elicit massive cardiomyocyte apoptosis via both extrinsic and intrinsic apoptotic pathways and cause severe cardiac dysfunction [7,8]. Previous studies also demonstrated that DOX could induce apoptosis via mechanisms that do not directly involve ROS production and oxidative stress [8].…”

miR‑144‑3p regulates the resistance of lung cancer to cisplatin by targeting Nrf2

“…miR-93 was able to regulate the oncogenic process in mammaries through regulation of its target gene NRF2 (16). MicroRNA-140-5p aggravated doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress by targeting Nrf2 and Sirt2 (17). Nevertheless, the biological role of miR-144-3p in modulating lung cancer drug resistance by targeting Nrf2 is not well understood.…”

MicroRNA‑495 regulates human gastric cancer cell apoptosis and migration through Akt and mTOR signaling

“…Gastric cancer is one of the most common malignancies in China, and its mortality is only second to lung cancer and liver cancer (1). A vast majority of clinically diagnosed cases are in the intermediate and advanced stage due to the lack of early specific symptoms and tumor markers for early detection and diagnosis, which has led to the high mortality of gastric cancer (13). Therefore, searching for tumor markers for the early screening or diagnosis of gastric cancer, together with developing agents with high efficiency and low toxicity is of great importance (14).…”