Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway

Chen, Hang; Zhu, Jing; Le, Yifei; Pan, Jieli; Liu, Ying; Liu, Zhijun; Wang, Cui; Dou, Xiaobing; Lu, Dezhao

doi:10.1016/j.phymed.2022.153964

Cited by 68 publications

(30 citation statements)

References 49 publications

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“…DOX induces oxidative stress in the cell membrane, which has been demonstrated using cardiomyocytes [3,4]. Studies have identified other mechanisms of cardiotoxicity including DNA intercalation, topoisomerase II inhibition, apoptosis, mitochondrial dysfunction, autophagy, ferroptosis and inflammatory cytokines, and calcium homeostasis [5][6][7][8][9]. However, most of these investigations were performed using cardiac myocytes, and thus the involvement of other cell types was poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

Store-operated calcium entry via ORAI1 regulates doxorubicin-induced apoptosis and prevents cardiotoxicity in cardiac fibroblasts

et al. 2022

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Despite exhibiting cardiotoxicity, doxorubicin (DOX) is widely used for cancer treatments. Cardiac fibroblasts (CFs) are important in the pathogenesis of heart failure. This necessitates the study of the effect of DOX on CFs. The impairment of calcium (Ca2+) homeostasis is a common mechanism of heart failure. Store-operated Ca2+ entry (SOCE) is a receptor-regulated Ca2⁺ entry pathway that maintains calcium balance by sensing reduced calcium stores in the endoplasmic reticulum. ORAI1, a calcium channel protein and the most important component of SOCE, is highly expressed in human cardiac fibroblasts (HCFs). It is upregulated in CFs from failing ventricles. However, whether ORAI1 in HCFs is increased and/or plays a role in DOX-induced cardiotoxicity remains unknown. In this study, we aimed to elucidate the relationship between ORAI1/SOCE and DOX-induced heart failure. Induction of apoptosis by DOX was characterized in HCFs. Apoptosis and cell cycle analyses were performed by fluorescence-activated cell sorting (FACS). Reactive oxygen species (ROS) production was measured using fluorescence. YM-58483 was used as an ORAI1/SOCE inhibitor. ORAI1-knockdown cells were established by RNA interference. In vivo experiments were performed by intraperitoneally injecting YM-58483 and DOX into mice. We first demonstrated that DOX significantly increased the protein expression level of p53 in HCFs by western blotting. FACS analysis revealed that DOX increased early apoptosis and induced cell cycle arrest in the G2 phase in fibroblasts. DOX also increased ROS production. DOX significantly increased the expression level of ORAI1 in CFs. Both YM-58483 and ORAI1 gene knockdown attenuated DOX-induced apoptosis. Similarly, YM-58483 attenuated cell cycle arrest in the G2 phase, and ORAI1 knockdown attenuated DOX-induced ROS production in HCFs. In the animal experiment, YM-58483 attenuated DOX-induced apoptosis. In HCFs, ORAI1/SOCE regulates p53 expression and plays an important role in DOX-induced cardiotoxicity. ORAI1 may serve as a new target for preventing DOX-induced heart failure.

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Section: Introductionmentioning

confidence: 99%

Store-operated calcium entry via ORAI1 regulates doxorubicin-induced apoptosis and prevents cardiotoxicity in cardiac fibroblasts

et al. 2022

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“…Ferroptosis as a new programmed mode of cell death has been reported involved in DIMI ( Li et al, 2021 ; Kitakata et al, 2022 ; Chen et al, 2022 ). Ferroptosis-related genes play a crucial role in regulation of ferroptosis in DIMI.…”

Section: Discussionmentioning

confidence: 99%

Construction of a ceRNA network of regulated ferroptosis in doxorubicin-induced myocardial injury

et al. 2023

PeerJ

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Background Ferroptosis and long-noncoding RNAs (lncRNAs) play crucial roles in doxorubicin (DOX)-induced myocardial injury (DIMI). Nevertheless, there is no research to construct competing endogenous RNAs (ceRNAs) network between lncRNAs and ferroptosis-related key gene. So our research was designed to screen ferroptosis-related genes from differentially expressed mRNAs in DIMI and construct lncRNAs regulated ferroptosis-related key gene ceRNAs network. Methods The male mice were injected with DOX intraperitoneally to induce myocardial injury, myocardial injury was evaluated by hematoxylin and eosin (HE) staining, and ferroptosis-related protein-glutathione peroxidase 4 (GPx4) protein expression was detected. The differentially expressed lncRNAs and mRNAs were detected by microarray, and the ferroptosis-related genes were screened to construct a protein-protein associations (PPA) network, the highest maximal clique centrality (MCC) score gene were identified by Cytoscape software, miRNAs bound to key genes and lncRNAs bound to miRNAs were predicted; then, the obtained lncRNAs were intersected with differentially expressed lncRNAs detected by microarray. Finally, the lncRNA/miRNA/mRNA ceRNA network of the highest MCC score gene regulating ferroptosis in DIMI was constructed. The expressions of the key components in ceRNA network were detected by qRT-PCR. Results Compared with the control group, in the DOX group, myocardial enzymes and HE staining showed that myocardium structure was changed, and GPx4 protein expression was decreased. The differentially expressed 10,265 lncRNAs and 6,610 mRNAs in the DOX group were detected via microarray. Among them, 114 ferroptosis-related genes were obtained to construct PPA networks, and Becn1 was identified as the key gene. Finally, the ceRNA network including Becn1, three miRNAs and four lncRNAs was constructed by predicting data of the Starbase database. The relative expressions of these components in ceRNA net were up-regulated and consistent with microarray results. Conclusions Based on the microarray detection results and bioinformatics analysis, we screened ferroptosis-related gene Becn1 and constructed the lncRNA/miRNA/mRNA ceRNA network of regulated ferroptosis in DIMI.

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“…Fisetin, an abundant flavonoid in fruits and vegetables, attenuated DOX-induced cardiomyopathy via the inhibition of ferroptosis by activating SIRT1/Nrf2 signaling [ 92 ]. Salidroside was also demonstrated to have a cardioprotective role in DOX-induced cardiomyopathy by significantly reducing ferroptotic cell death via AMPK-dependent signaling pathway activation [ 93 ]. The protective effect of dexrazoxane in the reduction of cytotoxicity in DOX-induced cardiomyopathy in rats was proven to inhibit ferroptosis by regulating high mobility group box 1 (HMGB1) [ 94 ].…”

Section: Iron-related Oxidative Stress and Mitochondrial Dysfunction ...mentioning

confidence: 99%

Role of Iron-Related Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Diseases

Fang

Xing

et al. 2022

Oxidative Medicine and Cellular Longevity

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Iron is indispensable in numerous biologic processes, but abnormal iron regulation and accumulation is related to pathological processes in cardiovascular diseases. However, the underlying mechanisms still need to be further explored. Iron plays a key role in metal-catalyzed oxidative reactions that generate reactive oxygen species (ROS), which can cause oxidative stress. As the center for oxygen and iron utilization, mitochondria are vulnerable to damage from iron-induced oxidative stress and participate in processes involved in iron-related damage in cardiovascular disease, although the mechanism remains unclear. In this review, the pathological roles of iron-related oxidative stress in cardiovascular diseases are summarized, and the potential effects and mechanisms of mitochondrial iron homeostasis and dysfunction in these diseases are especially highlighted.

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Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway

Cited by 68 publications

References 49 publications

Store-operated calcium entry via ORAI1 regulates doxorubicin-induced apoptosis and prevents cardiotoxicity in cardiac fibroblasts

Store-operated calcium entry via ORAI1 regulates doxorubicin-induced apoptosis and prevents cardiotoxicity in cardiac fibroblasts

Construction of a ceRNA network of regulated ferroptosis in doxorubicin-induced myocardial injury

Role of Iron-Related Oxidative Stress and Mitochondrial Dysfunction in Cardiovascular Diseases

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