Abstract
The clinical use of doxorubicin (DOX) is limited by its cardiotoxicity, which is closely associated with oxidative stress. Xinmailong (XML) is a bioactive peptide extracted from American cockroaches, which has been mainly applied to treat chronic heart failure in China. Our previous study showed that XML attenuates DOX-induced oxidative stress. However, the mechanism of XML in DOX-induced cardiotoxicity remains unclear. Heme oxygenase-1 (HO-1), an enzyme that is ubiquitously expressed in all cell types, has been found to take antioxidant effects in many cardiovascular diseases, and its expression is protectively upregulated under DOX treatment. Lysosome and autophagy are closely involved in oxidative stress as well. It is still unknown whether XML could attenuate doxorubicin-induced lysosomal dysfunction and oxidative stress in H9c2 cells via HO-1. Thus, this study was aimed at investigating the involvement of HO-1-mediated lysosomal function and autophagy flux in DOX-induced oxidative stress and cardiotoxicity in H9c2 cells. Our results showed that XML treatment markedly increased cell proliferation and SOD activity, improved lysosomal function, and ameliorated autophagy flux block in DOX-treated H9c2 cells. Furthermore, XML significantly increased HO-1 expression following DOX treatment. Importantly, HO-1-specific inhibitor (Znpp) or HO-1 siRNA could significantly attenuate the protective effects of XML against DOX-induced cell injury, oxidative stress, lysosomal dysfunction, and autophagy flux block. These results suggest that XML protects against DOX-induced cardiotoxicity through HO-1-mediated recovery of lysosomal function and autophagy flux and decreases oxidative stress, providing a novel mechanism responsible for the protection of XML against DOX-induced cardiomyopathy.
Highlights
Doxorubicin (DOX), a broad-spectrum anthracycline anticancer drug, is widely used in the chemotherapy of various tumors [1]
Our results showed that XML treatment markedly increased cell proliferation and superoxide dismutase (SOD) activity, improved lysosomal function, and ameliorated autophagy flux block in DOX-treated H9c2 cells
These results suggest that XML protects against DOX-induced cardiotoxicity through Heme oxygenase-1 (HO-1)-mediated recovery of lysosomal function and autophagy flux and decreases oxidative stress, providing a novel mechanism responsible for the protection of XML against DOX-induced cardiomyopathy
Summary
Doxorubicin (DOX), a broad-spectrum anthracycline anticancer drug, is widely used in the chemotherapy of various tumors [1]. Oxidative stress is considered an important cause of DOX-induced cardiotoxicity, which has been the prevailing hypothesis [3]. Lysosome and autophagy are closely involved in oxidative stress as well. The lysosome is responsible for cellular homeostasis through digesting unwanted materials in the cells [4]. Some articles have shown that DOX induces cellular changes consistent with autophagy initiation and autophagosome formation in cardiac cells. The fusion of the lysosome and autophagosome to form an autolysosome is a critical step during the process of autophagy, and accumulation of autolysosomes leads to increased reactive oxygen species (ROS) production [6]. Numerous endogenous or Oxidative Medicine and Cellular Longevity exogenous antioxidants can alleviate DOX-induced cardiotoxicity [7, 8]. Specific targets and mechanisms of oxidative stress remain to be identified
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