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Aims: Interleukin (IL) 9 is a pleiotropic cytokine, and recent studies have demonstrated that IL-9 is associated with several cardiovascular diseases, via regulation of the inflammatory response. Doxorubicin (DOX) is known to induce severe cardiac injury and dysfunction by enhancing inflammation. This study aimed to investigate the role of IL-9 in DOX-induced cardiotoxicity., Materials and Methods: DOX was used to induce cardiac dysfunction and the expression of IL-9 in the murine cardiac tissues was measured. The mice were intraperitoneally injected with recombinant mouse IL-9 (rmIL-9) or anti-IL-9 neutralizing antibody (IL-9nAb) for investigating the effect of IL-9 on DOX-induced cardiac injury and dysfunction. The messenger ribonucleic acid (mRNA) expression levels of the pro-inflammatory cytokines were determined in each group by quantitative real-time polymerase chain reaction (RT-qPCR). The effect of rmIL-9 or IL-9nAb on DOX-induced apoptosis was determined both in vivo and vitro., Key Findings: IL-9 levels significantly increased in the heart following DOX injection. Cardiac injury and dysfunction were induced by DOX, and treatment with IL-9nAb significantly alleviated DOX-induced injury, whereas rmIL-9 administration aggravated the cardiac damage. IL-9nAb decreased the expression of pro-inflammatory cytokines in the DOX-treated mice, while rmIL-9 administration increased the levels of pro-inflammatory cytokines. IL-9nAb reduced DOX-induced myocardial apoptosis, whereas rmIL-9 administration produced the opposite results. Additionally, IL-9nAb mitigated the DOX-induced apoptosis in H9C2 cells, while administration of rmIL-9 produced the opposite effect., Significance: Our results demonstrated that IL-9 aggravated DOX-induced cardiac injury and dysfunction by promoting the inflammatory response and cardiomyocyte apoptosis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Recent evidence has demonstrated that interleukin 12p35 knockout (IL-12p35 KO) is involved in cardiac diseases by regulating the inflammatory response. The involvement of inflammatory cells has also been observed in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate whether IL-12p35 KO affects DOX-induced cardiac injury and the underlying mechanisms., Methods: First, the effect of DOX treatment on cardiac IL-12p35 expression was assessed. In addition, to investigate the effect of IL-12p35 KO on DOX-induced cardiac injury, IL-12p35 KO mice were treated with DOX. Because IL-12p35 is the mutual subunit of IL-12 and IL-35, to determine the cytokine that mediates the effect of IL-12p35 KO on DOX-induced cardiac injury, mice were given phosphate-buffered saline (PBS), mouse recombinant IL-12 (rIL-12) or rIL-35 before treatment with DOX., Results: DOX treatment significantly increased the level of cardiac IL-12p35 expression. In addition, IL-12p35 KO mice exhibited higher serum and heart lactate dehydrogenase levels, higher serum and heart creatine kinase myocardial bound levels, and greater cardiac dysfunction than DOX-treated mice. Furthermore, IL-12p35 KO further increased M1 macrophage and decreased M2 macrophage differentiation, aggravated the imbalance of oxidants and antioxidants, and further activated the mitochondrial apoptotic pathway and endoplasmic reticulum stress autophagy pathway. Both rIL-12 and rIL-35 protected against DOX-induced cardiac injury by alleviating the inflammatory response, oxidative stress, apoptosis and autophagy., Conclusions: IL-12p35 KO aggravated DOX-induced cardiac injury by amplifying the levels of inflammation, oxidative stress, apoptosis and autophagy. (234 words)., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Doxorubicin (DOX)-induced cardiotoxicity impairs the quality of life of cancer patients during or after DOX treatment, and it is imperative to explore a novel strategy to address this problem. Resolvin E1 (RvE1) is derived from eicosapentaenoic acid (EPA), which has been reported to exert beneficial effects on DOX-induced oxidative stress in cardiomyocytes. This study was designed to investigate whether RvE1 protects against DOX-induced cardiotoxicity, and the underlying mechanism was explored. DOX (20 mg/kg, one injection, i.p.) was used to induce DOX-induced cardiotoxicity in C57BL/6 mice. At 5 days after DOX administration, the effect of RvE1 was assessed by measuring cardiac function, oxidative stress, autophagy and apoptosis in cardiac tissue. We used an AKT inhibitor and rapamycin to investigate the underlying mechanisms. Our results showed that RvE1 inhibited the DOX-induced decrease in body weight and heart weight, the reduction in left ventricular ejection fraction and fractional shortening, and the increase in lactate dehydrogenase, creatine kinase myocardial bound and cardiomyocyte vacuolization. Compared to the control group, the DOX group exhibited increased oxidative stress, autophagy and apoptosis in cardiac tissue, which were alleviated by treatment with RvE1. The AKT/mTOR signaling pathways were responsible for RvE1-mediated regulation of DOX-induced oxidative stress, autophagy and myocardial apoptosis. In conclusion, RvE1 protected against DOX-induced cardiotoxicity via the regulation of AKT/mTOR signaling. [ABSTRACT FROM AUTHOR]