Abstract
Resolvin D1 (RvD1) is a lipid mediator that promotes resolution of inflammation. However, the function of RvD1 in doxorubicin- (Dox-) induced cardiotoxicity remains to be clarified. This study aimed to investigate whether RvD1 could attenuate Dox-induced cardiac injury. The mice were divided into three groups: control, Dox (20 mg/kg, once, intraperitoneally), and Dox + RvD1. RvD1 (2.5 μg/kg, intraperitoneally) was injected daily for 5 days. Echocardiography was performed to evaluate the cardiac function, and the heart tissue and serum samples were collected for further analyses. The results showed that RvD1 attenuated the decreased ratio of heart weight/body weight and heart weight/tibia length, the increased level of creatine kinase and activity of lactate dehydrogenase after Dox treatment. RvD1 improved the ejection fraction and fractional shortening of left ventricular and attenuated the severity of apoptosis induced by Dox. As for the underlying pathways, the results showed that RvD1 reduced the expression of IL-1 and IL-6, and attenuated the phosphorylation of P65 in cardiac tissue. RvD1 attenuated the oxidative stress induced by Dox, as demonstrated by the attenuated levels of superoxide dismutase, glutathione, and malondialdehyde, decreased expression of Nox-2 and Nox-4 and increased expression of Nrf-2 and HO-1. In addition, RvD1 also inhibited the endoplasmic reticulum stress induced by Dox. These results indicate the potential therapeutic benefits of RvD1 in Dox-induced cardiotoxicity in mice, and the mechanism may be related to the attenuated inflammation, oxidative stress and endoplasmic reticulum stress.
Highlights
Doxorubicin (Dox), an anthracycline-based chemotherapeutic drug, is routinely used in the treatment of a wide variety of cancers, including breast, ovarian, bladder, lung, thyroid, and stomach cancer (Buzdar et al, 1985)
This study revealed that Resolvin D1 (RvD1) attenuates Dox-induced cardiotoxicity
The possible mechanisms involved in RvD1mediated attenuation of Dox-induced cardiotoxicity include regulation of inflammation, oxidative stress, autophagy dysfunction, ER stress, and apoptosis
Summary
Doxorubicin (Dox), an anthracycline-based chemotherapeutic drug, is routinely used in the treatment of a wide variety of cancers, including breast, ovarian, bladder, lung, thyroid, and stomach cancer (Buzdar et al, 1985). Treatment with Dox has been reported to cause dose-dependent cardiac toxicity and heart failure (Lefrak et al, 1973). Dox-induced cardiotoxicity seriously impairs the quality of life and life expectancy of patients with cancer. Several studies have shown that oxidative stress and apoptosis of cardiomyocytes are associated with Dox-induced cardiotoxicity (Kalivendi et al, 2001). There are currently no effective drugs to prevent and treat the cardiotoxicity caused by Dox
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