In:
Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 9 ( 2023-1-11)
Abstract:
The mechanisms of doxorubicin (DOX) cardiotoxicity were complex and controversial, with various contradictions between experimental and clinical data. Understanding the differences in the molecular mechanism between DOX-induced acute and chronic cardiotoxicity may be an ideal entry point to solve this dilemma. Methods Mice were injected intraperitoneally with DOX [(20 mg/kg, once) or (5 mg/kg/week, three times)] to construct acute and chronic cardiotoxicity models, respectively. Survival record and ultrasound monitored the cardiac function. The corresponding left ventricular (LV) myocardium tissues were analyzed by RNA-seq to identify differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) found the key biological processes and signaling pathways. DOX cardiotoxicity datasets from the Gene expression omnibus (GEO) database were combined with RNA-seq to identify the common genes. Cytoscape analyzed the hub genes, which were validated by quantitative real-time PCR. ImmuCo and ImmGen databases analyzed the correlations between hub genes and immunity-relative markers in immune cells. Cibersort analyzed the immune infiltration and correlations between the hub genes and the immune cells. Logistic regression, receiver operator characteristic curve, and artificial neural network analysis evaluated the diagnosis ability of hub genes for clinical data in the GEO dataset. Results The survival curves and ultrasound monitoring demonstrated that cardiotoxicity models were constructed successfully. In the acute model, 788 DEGs were enriched in the activated metabolism and the suppressed immunity-associated signaling pathways. Three hub genes (Alas1, Atp5g1, and Ptgds) were upregulated and were negatively correlated with a colony of immune-activating cells. However, in the chronic model, 281 DEGs showed that G protein-coupled receptor (GPCR)-related signaling pathways were the critical events. Three hub genes (Hsph1, Abcb1a, and Vegfa) were increased in the chronic model. Furthermore, Hsph1 combined with Vegfa was positively correlated with dilated cardiomyopathy (DCM)-induced heart failure (HF) and had high accuracy in the diagnosis of DCM-induced HF (AUC = 0.898, P = 0.000). Conclusion Alas1, Atp5g1, and Ptgds were ideal biomarkers in DOX acute cardiotoxicity. However, Hsph1 and Vegfa were potential biomarkers in the myocardium in the chronic model. Our research, first, provided bioinformatics and clinical evidence for the discovery of the differences in mechanism and potential biomarkers of DOX-induced acute and chronic cardiotoxicity to find a therapeutic strategy precisely.
Type of Medium:
Online Resource
ISSN:
2297-055X
DOI:
10.3389/fcvm.2022.996809
DOI:
10.3389/fcvm.2022.996809.s001
DOI:
10.3389/fcvm.2022.996809.s002
DOI:
10.3389/fcvm.2022.996809.s003
DOI:
10.3389/fcvm.2022.996809.s004
DOI:
10.3389/fcvm.2022.996809.s005
DOI:
10.3389/fcvm.2022.996809.s006
DOI:
10.3389/fcvm.2022.996809.s007
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2023
detail.hit.zdb_id:
2781496-8
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