The mechanism of cardiotoxicity induced by evodiamine and matrine was revealed by epitranscriptomics
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE274753 | GEO | 2024/08/20
REPOSITORIES: GEO
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Project description:Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC).
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Project description:Improvements in the diagnosis and treatment of cancer has revealed the long-term side effects of chemotherapeutics, particularly cardiotoxicity. Current clinical measures to track cardiotoxicity are insufficient to diagnose damage before it has been done, necessitating new, early biomarkers of cardiotoxicity. Here, we collected paired transcriptomics and metabolomics data characterizing in vitro cardiotoxicity to three compounds: 5-fluorouracil, acetaminophen, and doxorubicin. Standard gene enrichment and metabolomics approaches identify some commonly affected pathways and metabolites but are not able to readily identify mechanisms of cardiotoxicity. Here, we integrate this paired data with a genome-scale metabolic network reconstruction (GENRE) of the heart to identify shifted metabolic functions, unique metabolic reactions, and changes in flux in metabolic reactions in response to these compounds. Using this approach, we are able to confirm known mechanisms of doxorubicin-induced cardiotoxicity and provide hypotheses for mechanisms of cardiotoxicity for 5-fluorouracil and acetaminophen.
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Project description:The use of tubulin binders (TBs) in oncology indications often is associated with cardiotoxicity, the mechanism of which has not been elucidated. We observed that a single administration of TBs to rats caused an increase in the number of mitotic figures in the myocardial interstitium after 24 hours. We therefore hypothesized that interstitial cells are the primary target of TBs. To test this hypothesis, we evaluated the acute effects of a single intravenous administration of 3 reference TBs, colchicine (0.2 and 2 mg/kg), vinblastine (0.5 and 3 mg/kg), and vincristine (0.1 and 1 mg/kg) 6 and 24 hours after dosing. Mitotic arrest was identified at 24 hours in all high-dose groups based on an increase in the number of mitotic figures in the interstitium coupled with a dramatic decrease in the number of Ki67-positive interstitial cells. Analysis of the myocardial transcriptomic data further supported G2/M cell cycle arrest 6 hours after dosing with the high-dose groups of all 3 compounds. Apoptotic figures and an increase in the number of cleaved caspase 3-positive cells were identified at 6 and 24 hours at the highest dose of each compound almost exclusively in interstitial cells; a few cardiomyocytes were affected as well. Transcriptomic data further suggested that some of the affected interstitial cells were endothelial cells based on the up-regulation of genes typically associated with vascular damage and down-regulation of Endothelial Cell-Specific Molecule 1 and Apelin. Taken together, these data identify endothelial cells of the myocardium as the primary target of the cardiotoxicity of TBs and identify cell cycle arrest as the mechanism of this toxicity. Gene expression was profiled in the myocardium of rats at 6 and 24 hr after a single dose of colchicine, vinblastine or vincristine.
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Project description:Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tVNS improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 248 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.
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Project description:Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin (DOXO), Aclarubicin (ACLA) and Amrubicin (AMR). DOXO and ACLA unlike AMR substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated with anthracyclines annually.
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Project description:Recent advances in RNA biology have focused on a new layer of gene expression regulation termed Epitranscriptomics. One of the most common mRNA modifications that is highly abundant in brain is N6-methyladenosine (m6A), which has been involved in learning and memory processes. Indeed, different studies have shown that m6A levels vary in response to cognitive tasks. This mark is dynamically regulated by a multicomplex of methyltransferases (METTL3, METTL14 and WTAP) as well as a series of demethylases (FTO and ALKBH5). Given the early cognitive symptomatology in Huntington’s Disease (HD), we aimed to determine whether expression of mutant huntingtin (mHtt) induces changes in the m6A epitranscriptome profile and signaling, leading to the memory and learning deficits observed in HD. For this purpose, genetically modified HdhQ7/Q111 mice were subjected to a hippocampal training task and relative levels of the m6A-modifying proteins were determined in different cellular compartments. In addition, identity of mRNAs with altered m6A profiles was determined through methylated RNA immunoprecipitation sequencing (meRIP-seq). Our results have shown that symptomatic HD mice display altered levels of FTO and METTL14, both in the nuclear as well as in the synaptic compartment. Moreover, transcriptome-wide profiling of m6A-modifed mRNAs has revealed a more prominent decrease in methylated peaks in HD mice in response to a training task when compared to age-matched wild type (WT) littermates. Interestingly, genes that show differential m6A peaks include immediate early genes and genes involved in synapse and neuronal function, among others. Thus, our results suggest that the altered levels of the m6A-modifying machinery in HD mice could be leading to a differential epitranscriptomic profile, contributing to the cognitive symptomatology observed in those animals. Altogether, our data uncover a promising role of m6A as a novel hallmark of the disease, pointing to this RNA chemical modification as a potential target to improve cognitive disturbances among HD patients
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