Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice

Tanaka, Yoshiro; Nagoshi, Tomohisa; Yoshii, Akira; Oi, Yuhei; H, Takahashi; Kimura, Haruka; Ito, Keiichi; Kashiwagi, Yusuke; Tanaka, Toshikazu; Yoshimura, Michihiro

doi:10.1016/j.freeradbiomed.2020.10.303

Cited by 32 publications

(23 citation statements)

References 60 publications

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“…The plasma UA level was measured at 4 weeks after the initiation of dotinurad treatment using a UA assay kit (Sigma) according to the manufacturer's protocol as described previously [ 3 ].…”

Section: Methodsmentioning

confidence: 99%

“…Increasing evidence indicates that elevated serum uric acid (UA) levels are associated with several cardiovascular diseases, chronic kidney disease, and nonalcoholic fatty liver disease (NAFLD) [ [1] , [2] , [3] ]. Patients with hyperuricemia are also predisposed to metabolic syndrome, a pathological condition that involves insulin resistance, chronic inflammation, and the synthesis of reactive oxygen species (ROS) [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

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URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

Tanaka

Nagoshi

et al. 2022

Molecular Metabolism

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Objective Accumulating evidence indicates that high uric acid (UA) is strongly associated with obesity and metabolic syndrome and drives the development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidneys, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. We herein investigated the role and functional significance of URAT1 in diet-induced obese mice. Methods Mice fed a high-fat diet (HFD) for 16–18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks. Results We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than the kidneys. Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (chemokine ligand 2 (Ccl2) and tissue necrosis factor α (TNFα)), all of which were attenuated by dotinurad. Similarly, HFD significantly increased URAT1 expression in BAT, resulting in lipid accumulation (whitening of BAT), and increased the production of tissue reactive oxygen species (ROS), which were reduced by dotinurad via UCP1 activation. Conclusions In conclusion, a novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

Tanaka

Nagoshi

et al. 2022

Molecular Metabolism

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“…Treatment with EMPA during exposure to DOXO reduced significantly ferroptosis and MDA content in the heart, especially in the cardiac mitochondrial fraction (5.6 ± 2.6 vs 15.2 ± 3.3 for DOXO group; p < 0.001). The recent study by Tanaka et al [31] showed that the increased oxidative stress induced by tissue xanthine oxidase activation is deeply involved in doxorubicin-induced cells/well seeded in a 24-well plate) untreated (control) or treated with gallic acid (as positive antioxidant control), EMPA (10, 50, 500 nM), LPS (40 ng/ml) or DOXO (100 nM) alone or co-incubated with EMPA at 10, 50 and 500 nM. One-way ANOVA.…”

Section: Effects On Ferroptosis Xanthine Oxidase and Pro-inflammatory Biomarkersmentioning

confidence: 96%

“…Increasing evidence indicates that ferroptosis plays a critical role in doxorubicin-induced cardiotoxicity [29][30][31]; therefore, we aimed to test the effect of EMPA on ferroptosis during DOXO treatment. Mitochondrial lipid peroxidation was measured using MitoPeDPP test (a fluorescence probe that specifically reacts with lipid peroxides in the mitochondrial inner membrane (Dojindo).…”

Section: Ferroptosis Assay: Measurements Of Mitochondrial Lipid Peroxidation Using Mitopedpp and Mda Content In Cytosolic And Mitochondrimentioning

confidence: 99%

“…The recent study by Tanaka et al showed that the increased oxidative stress induced by tissue xanthine oxidase activation is deeply involved in doxorubicininduced cardiotoxicity [31]. The xanthine oxidase activities in heart tissues were measured using the horseradish peroxidase-linked Amplex Red fluorescence assay kit (Molecular Probes, Invitrogen Detection Technologies), according to the manufacturer's instructions.…”

Section: Xanthine Oxidase Activitiesmentioning

confidence: 99%

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The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

Quagliariello

Laurentiis

Rea

et al. 2021

Cardiovasc Diabetol

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132

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Background Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA‐REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of EMPA in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analysed. We aimed to evaluate the effects of EMPA on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and MyD88-related pathways resulting in anti-apoptotic and anti-fibrotic effects. Methods Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to EMPA. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studies were also performed: expression of NLRP3 inflammasome, MyD88 myddosome and p65/NF-κB associated to secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin (DOXO, n = 6), EMPA (EMPA, n = 6) or doxorubicin combined to EMPA (DOXO-EMPA, n = 6). DOXO was injected intraperitoneally. Ferroptosis and xanthine oxidase were studied before and after treatments. Cardiac function studies, including EF, FS and radial/longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac fibrosis and apoptosis were histologically studied through Picrosirius red and TUNEL assay, respectively and quantified through pro-collagen-1α1, MMP-9 and Caspase-3 expression. Tissue NLRP3, MyD88 and cytokines were also quantified before and after treatments through ELISA methods. Results Cardiomyocytes exposed to doxorubicin increased the intracellular Ca2+ content and expression of several pro-inflammatory markers associated to cell death; co-incubation with EMPA reduced significantly the magnitude of the effects. In preclinical study, EMPA increased EF and FS compared to DOXO groups (p < 0.05), prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin (RS) 30.3% in EMPA-DOXO vs 15.7% in DOXO mice; LS − 17% in EMPA-DOXO vs – 11.7% in DOXO mice (p < 0.001 for both). Significant reductions in ferroptosis, xanthine oxidase expression, cardiac fibrosis and apoptosis in EMPA associated to DOXO were also seen. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart, liver and kidneys was also seen in DOXO-EMPA group compared to DOXO (p < 0.001). Conclusion EMPA reduced ferroptosis, fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in significant improvements in cardiac functions. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.

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Recent advances in pluripotent stem cell-derived cardiac organoids and heart-on-chip applications for studying anti-cancer drug-induced cardiotoxicity

Liu,

Fang,

Zhong

et al. 2023

Cell Biol Toxicol

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Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice

Cited by 32 publications

References 60 publications

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

Recent advances in pluripotent stem cell-derived cardiac organoids and heart-on-chip applications for studying anti-cancer drug-induced cardiotoxicity

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