Calycosin Alleviates Doxorubicin-Induced Cardiotoxicity and Pyroptosis by Inhibiting NLRP3 Inflammasome Activation.

Lei Zhang,Yi-Tao Xue,Juan Zhang,Jie Cui,Qian Zhang,Meng-Qi Yang,Cundong Fan,Yan Li,Yong-Hao Jiang,Hua-Chen Jiao,Yang Liu,Yue-Hua Jiang,J L Franco

doi:10.1155/2022/1733834

Abstract

Calycosin (CAL) is the main active component present in Astragalus and reportedly possesses diverse pharmacological properties. However, the cardioprotective effect and underlying mechanism of CAL against doxorubicin- (DOX-) induced cardiotoxicity need to be comprehensively examined. Herein, we aimed to investigate whether the cardioprotective effects of CAL are related to its antipyroptotic effect. A cardiatoxicity model was established by stimulating H9c2 cells and C57BL/6J mice using DOX. In vitro, CAL increased H9c2 cell viability and decreased DOX-induced pyroptosis via NLRP3, caspase-1, and gasdermin D signaling pathways in a dose-dependent manner. In vivo, CAL-DOX cotreatment effectively suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis via the same molecular mechanism. Next, we used nigericin (Nig) and NLRP3 forced overexpression to determine whether CAL imparts antipyroptotic effects by inhibiting the NLRP3 inflammasome in vitro. Furthermore, CAL suppressed DOX-induced mitochondrial oxidative stress injury in H9c2 cells by decreasing the generation of reactive oxygen species and increasing mitochondrial membrane potential and adenosine triphosphate. Likewise, CAL attenuated the DOX-induced increase in malondialdehyde content and decreased superoxide dismutase and glutathione peroxidase activities in H9c2 cells. In vivo, CAL afforded a protective effect against DOX-induced cardiac injury by improving myocardial function, inhibiting brain natriuretic peptide, and improving the changes of the histological morphology of DOX-treated mice. Collectively, our findings confirmed that CAL alleviates DOX-induced cardiotoxicity and pyroptosis by inhibiting NLRP3 inflammasome activation in vivo and in vitro.

Highlights

Doxorubicin (DOX) has a wide therapeutic range with demonstrated efficacy against various cancers; its dosedependent cardiotoxicity greatly limits its clinical application
Lactate Dehydrogenase (LDH) release, improved cell morphology, and increased cell number. Nigericin reversed these CAL-induced changes (Supplementary Figure 2(b)–2(d)). These results indicated that CAL exerts cardioprotective effects by inhibiting the NLR family pyrin domain 3 (NLRP3) inflammasome
Several pathogenic mechanisms have been implicated in DOX-induced cardiotoxicity, such as oxidative stress, mitochondrial dysfunction, inflammation, autophagy, apoptosis [26], pyroptosis [27], and ferroptosis [28]; the findings remain controversial

Summary

Introduction

Doxorubicin (DOX) has a wide therapeutic range with demonstrated efficacy against various cancers; its dosedependent cardiotoxicity greatly limits its clinical application. The potential mechanism of DOX-mediated cardiotoxicity has mainly focused on oxidative stress, mitochondrial dysfunction, and altered Ca2+ homeostasis [2]. Mitochondrial dysfunction increases the generation of intracellular reactive oxygen species (ROS), and oxidative stress remains well-elucidated [3]. Oxidative Medicine and Cellular Longevity needs to be comprehensively examined [4,5,6]. Several drugs have been shown to prevent adverse effects of DOX-induced cardiotoxicity [7,8,9], dexrazoxane is the only U.S Food and Drug Administration- (FDA-) approved drug for treating DOX-induced cardiotoxicity [10]. More effective therapeutic agents and strategies are needed to prevent and manage this challenge

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