Dataset Information

Choline Protects the Heart from Doxorubicin-Induced Cardiotoxicity through Vagal Activation and Nrf2/HO-1 Pathway.

ABSTRACT: Choline is a precursor of the major neurotransmitter acetylcholine and has been demonstrated beneficial in diverse models of cardiovascular disease. Here, we sought to verify that choline protects the heart from DOX-induced cardiotoxicity and the underlying mechanisms. The results showed that DOX treatment decreased left ventricular ejection fraction and fractional shortening and increased serum cardiac markers and myocardial fibrosis, which were alleviated by cotreatment with choline. DOX-induced cardiotoxicity was accompanied by increases in oxidative stress, inflammation, and apoptosis, which were rectified by choline cotreatment. Levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme-oxygenase-1 (HO-1), which are antioxidant markers, were lowered by DOX and upregulated by choline. Moreover, DOX significantly decreased serum acetylcholine levels and the high-frequency component of heart rate variability and increased serum norepinephrine levels and the low-frequency component; these effects were rescued by choline administration. Interestingly, the protective effects of choline could be partially reversed by administration of the muscarinic receptor antagonist atropine. This suggests that choline might be a promising adjunct therapeutic agent to alleviate DOX-induced cardiotoxicity.

SUBMITTER: Guo F

PROVIDER: S-EPMC9005275 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Choline Protects the Heart from Doxorubicin-Induced Cardiotoxicity through Vagal Activation and Nrf2/HO-1 Pathway.

Guo Fuding F Wang Yueyi Y Wang Jun J Liu Zhihao Z Lai Yanqiu Y Zhou Zhen Z Liu Zihan Z Zhou Yuyang Y Xu Xiao X Li Zeyan Z Wang Meng M Yu Fu F Hu Ruijie R Zhou Liping L Jiang Hong H

Oxidative medicine and cellular longevity 20220405

Choline is a precursor of the major neurotransmitter acetylcholine and has been demonstrated beneficial in diverse models of cardiovascular disease. Here, we sought to verify that choline protects the heart from DOX-induced cardiotoxicity and the underlying mechanisms. The results showed that DOX treatment decreased left ventricular ejection fraction and fractional shortening and increased serum cardiac markers and myocardial fibrosis, which were alleviated by cotreatment with choline. DOX-induc ...[more]

PMID: 35422894

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Project description:AimsDoxorubicin (DOX) is a potent anticancer drug; however, it is associated with significant cardiotoxicity. CDC20 is an E3 ubiquitin ligase that plays a role in cell cycle progression and apoptosis in various types of cancers. The involvement of CDC20 in DOX-induced cardiotoxicity (DIC) is poorly understood. Hence, this study aimed to explore the potential role of CDC20 in the development of DIC and assess whether CDC20 influences the antitumor effects of DOX.Methods and resultsH9C2 cells were treated with DOX, followed by transcriptomic analysis to identify differentially expressed genes. C57BL/6 mice were treated with DOX for 4 weeks after tail vein injection of CDC20 myocardial-specific knockout mice, AAV9-cTNT-(si) CDC20, or intraperitoneal injection of apcin. Cardiac function and pathological changes were evaluated by echocardiography and pathological staining, respectively. The influence of CDC20 on DOX-induced tumor inhibition was assessed in tumor-bearing mice. In vitro analysis involved treating cardiomyocytes with the Ad-CDC20 adenovirus and DOX, followed by proteomic and ubiquitination-related assays to identify potential downstream ubiquitinated CDC20 proteins. Additionally, we investigated the effect of CCDC69 on CDC20-mediated protection against DOX-induced apoptosis using CCDC69 shRNA. Transcriptome analysis revealed that DOX effectively suppressed the expression of CDC20. Cardiomyocyte-specific overexpression of CDC20 in a DOX-induced mouse model of myocardial injury effectively mitigated cardiomyocyte apoptosis, inflammation, fibrosis, and cell atrophy. Our mechanistic investigation revealed that CDC20 attenuates DOX-induced apoptosis by downregulating CCDC69 expression. Moreover, cardiomyocyte-specific overexpression of CDC20 had no effect on the therapeutic efficacy of DOX against tumors.ConclusionOur findings indicate that CDC20 safeguards the heart against DOX-induced cardiotoxicity by modulating CCDC69 degradation without compromising the antitumor efficacy of DOX.

Dataset Information

Choline Protects the Heart from Doxorubicin-Induced Cardiotoxicity through Vagal Activation and Nrf2/HO-1 Pathway.

Publications

Choline Protects the Heart from Doxorubicin-Induced Cardiotoxicity through Vagal Activation and Nrf2/HO-1 Pathway.

Similar Datasets

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