MicroRNA‐495‐3p diminishes doxorubicin‐induced cardiotoxicity through activating AKT

Abstract

Doxorubicin (Dox) is identified as a broad-spectrum and efficient chemotherapeutic agent for multiple human solid and hematopoietic cancers; however, adverse cardiovascular events due to the cumulative cardiotoxicity extremely impede its clinical use. [1][2][3] Despite the exact mechanisms of Dox-induced cardiotoxicity remain unclear, reactive oxygen species (ROS) overproduction and oxidative damage are implicated in the pathogenesis of Doxinduced cardiotoxicity. 4,5 Zhang et al. 6 previously has revealed that Dox forms a ternary cleavage complex with topoisomerase-II beta and DNA, which subsequently destroys the structure and function of mitochondria, and leads to excessive ROS generation. In addition, Dox treatment can increase the accumulation of iron inside the mitochondria, and then promote ROS amplification through a Fenton reaction. 7 Moreover, the heart is especially vulnerable to oxidative damage due to the less active antioxidant defence and negligible regenerative capability. 8 Accordingly, our recent study demonstrated that inhibiting oxidative stress significantly prevented Dox-induced cardiotoxicity and dysfunction. 9 Therefore, it is reasonable to treat Dox-induced cardiotoxicity through inhibiting oxidative stress.

MicroRNAs in doxorubicin-induced cardiotoxicity: The DNA damage response

“…Therefore, DOX-induced miR-25 upregulation might attenuate AMPK signaling via targeting PTEN. However, as mentioned in the next section, PTEN inhibition and AKT activation have also been reported to be cardioprotective against DIC ( Yu et al, 2020 ; Meng and Xu, 2022 ). Further testing is required to determine whether the harmful effect of miR-25 depends on the alteration of AMPK or AKT pathways.…”

“…Meanwhile, some miRNAs have been reported as AKT activators and may counteract DIC. These are, for example, miR-495-3p, miR-17-5p, and miR-21 ( Tong et al, 2015 ; Yu et al, 2020 ; Meng and Xu, 2022 ). MiR-495-3p expression is downregulated in DOX-treated hearts, and it targets PTEN to activate AKT signaling ( Meng and Xu, 2022 ).…”

“…These are, for example, miR-495-3p, miR-17-5p, and miR-21 ( Tong et al, 2015 ; Yu et al, 2020 ; Meng and Xu, 2022 ). MiR-495-3p expression is downregulated in DOX-treated hearts, and it targets PTEN to activate AKT signaling ( Meng and Xu, 2022 ). Unlike miR-25, this PTEN inhibition attenuated DOX-induced oxidative stress and DIC.…”

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity

“…Additionally, miR-30e, miR-486, and miR-495-3p target PTEN, which opposes the PI3K/AKT pathway, resulting in decreased apoptosis. 90 , 93 , 94 In a mouse model of hypoxia/reperfusion injury, miR-486 overexpression resulted in a decrease in apoptotic cardiomyocytes and infarct size. 90 miR-20a protected cardiomyocytes from apoptosis in vitro, and in diabetic rats, overexpression of miR-20a attenuated cardiac dysfunction by targeting Rock2 and Egln3.…”

Noncoding RNAs and Cardiac Fibrosis

“…MiR-133b attenuated polypyrimidine tract bundle-binding protein 1 and transgelin 2 to regulate apoptosis and mediate cardiac fibrosis induced by adriamycin, implying that miR-133b may be a potential biomarker of adriamycin-induced cardiac injury [33]. Endogenous miR-495-3p protects cells against DOX-induced cardiotoxicity by activating the AKT pathway in vivo and in vitro [36]. In addition, the expression of the lncRNA KCNQ1OT1 downregulated fusion-type sarcoma in oocytes and reduced the myocardial fibrosis area in DOX-treated mouse models [61].…”