Toll-like receptor 5 deficiency diminishes doxorubicin-induced acute cardiotoxicity in mice

Ma, Zhen‐Guo; Kong, Chun-Yan; Wu, Hongyan; Song, Peng; Zhang, Xin; Yao, Yuan; Deng, Wei; Tang, Qi‐Zhu

doi:10.7150/thno.47516

Cited by 39 publications

(34 citation statements)

References 55 publications

(64 reference statements)

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“…These findings were consistent with a previous study [ 30 ]. Using NAC, we found that ROS depletion abolished the accumulation of inflammation and NF- κ B activation caused by miR-152 inhibition, suggesting that the inflammatory response was secondary to the production of ROS in miR-152-deficient cardiomyocytes, which was also in line with a recent study found that inflammatory response was not the main biological factor and secondary to ROS production during acute DOX injury [ 31 ]. DOX-induced accumulation of ROS resulted in cytochrome c release followed by caspase-3 activation and cell apoptosis [ 10 ].…”

Section: Discussionsupporting

confidence: 86%

Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

Zhang

Lai

Guo

2021

Oxidative Medicine and Cellular Longevity

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Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.

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Section: Discussionsupporting

confidence: 86%

Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

Zhang

Lai

Guo

2021

Oxidative Medicine and Cellular Longevity

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“…Various treatment regimens have been reported to study doxorubicin cardiotoxicity in mouse models, including using very low-dose doxorubicin to avoid systemic toxicity [33]. We used an acute cardiotoxicity model that was induced by single injection of doxorubicin [24,[34][35][36][37]. TRIM21 +/+ and TRIM21 À/À C57BL/6J male mice (10-12 week) were randomly divided into two groups: one was injected intraperitoneally (i.p.)…”

Section: Loss Of Trim21 Has Cardio-protective Effects In Two Mouse Models Of Cardiac Injurymentioning

confidence: 99%

Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin

et al. 2021

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Background: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage. Methods: Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin. Findings: TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicininduced cell death. Interpretation: Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity.

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“…However, its clinical use is hampered due to its acute and chronic cardiotoxic effects, as long-term use of DOX can result in left ventricular dysfunction and ultimately heart failure ( 2 , 3 ). Previous studies have revealed that DOX treatment leads to excess free radicals and reactive oxygen species (ROS) in the myocardium ( 4 , 5 ). These radicals induce potential redox-associated damage through both enzymatic and non-enzymatic pathways ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Benazepril hydrochloride protects against doxorubicin cardiotoxicity by regulating the PI3K/Akt pathway

et al. 2021

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Doxorubicin (DOX) stimulates the generation of reactive oxygen species, thereby impairing mitochondrial functions. Angiotensin-converting enzyme inhibitors (ACEIs) have been identified to exhibit protective effects on cardiovascular diseases. The present study aimed to test the hypothesis that an ACEI benazepril hydrochloride (HCl) may protect against DOX-induced cardiotoxicity. The DOX injury model was established using rat embryonic cardiac myoblast cells (H9c2 cell line) treated with DOX in vitro. H9c2 cells were treated with benazepril-HCl, DOX or a mixture of DOX and benazepril-HCl to measure the activities of myocardial enzymes including lactate dehydrogenase (LDH), superoxide dismutase, catalase and glutathione peroxidase, in addition to the concentration of malondialdehyde in the culture medium. Cells without any treatment were used as a control. DOX treatment increased the levels of activity of myocardial enzymes in H9c2 cells compared with those in the untreated control cells. Additionally, co-treatment with benazepril-HCl significantly reduced the levels of apoptosis occurring due to DOX-mediated cellular damage. The mechanistic experiment revealed that pretreatment with benazepril-HCl counteracted the DOX-induced oxidative stress and suppressed the activation of apoptosis via the PI3K/Akt signaling pathway. By contrast, an Akt inhibitor (MK2206) inhibited the protective effects of benazepril-HCl against DOX-induced H9c2 cell injury, as revealed by increased LDH release in H9c2 cells. These results suggested that benazepril-HCl may potentially be administered as an adjuvant for DOX in long-term clinical use.

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Toll-like receptor 5 deficiency diminishes doxorubicin-induced acute cardiotoxicity in mice

Cited by 39 publications

References 55 publications

Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

Activation of Nrf2 by miR‐152 Inhibits Doxorubicin‐Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin

Benazepril hydrochloride protects against doxorubicin cardiotoxicity by regulating the PI3K/Akt pathway

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