2. Academic Validation
  3. Identification of autophagy-related signatures in doxorubicin-induced cardiotoxicity

Identification of autophagy-related signatures in doxorubicin-induced cardiotoxicity

  • Toxicol Appl Pharmacol. 2024 Oct:491:117082. doi: 10.1016/j.taap.2024.117082.
Haiyan Wu 1,  Haoqiang Chen 2,  Xiaoxue Ding 2,  Xiaohui Kuang 2,  Mingjie Pang 2,  Suijuan Liu 2,  Yan Zhang 3,  Qian Wang 2,  Kunzhi Li 4,  Hong Zhang 5
Affiliations

Affiliations

  • 1 Faculty of Life Science and Technology, Kunming University of Science and Technology, No. 727 Jingming South Road, Kunming 650500, P.R.China; Department of Cardiovascular Medicine, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming 650032, P.R.China.
  • 2 Department of Cardiovascular Medicine, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming 650032, P.R.China.
  • 3 Department of Magnetic Resonance lmaging, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming, 650032, P.R. China.
  • 4 Faculty of Life Science and Technology, Kunming University of Science and Technology, No. 727 Jingming South Road, Kunming 650500, P.R.China. Electronic address: likunzhikg@163.com.
  • 5 Department of Cardiovascular Medicine, The First People's Hospital of Yunnan Province/The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming 650032, P.R.China. Electronic address: zhanghong_ypfph@163.com.
PMID: 39218162 DOI: 10.1016/j.taap.2024.117082
Abstract

Purpose: Doxorubicin is an Antibiotic drug used clinically to treat infectious diseases and tumors. Unfortunately, it is cardiotoxic. Autophagy is a cellular self-decomposition process that is essential for maintaining homeostasis in the internal environment. Accordingly, the present study was proposed to characterize the autophagy-related signatures of doxorubicin-induced cardiotoxicity.

Methods: Datasets related to doxorubicin-induced cardiotoxicity were retrieved by searching the GEO database and differentially expressed genes (DEGs) were identified. DEGs were taken to intersect with autophagy-related genes to obtain autophagy-related signatures, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network were performed on them. Further, construction of miRNA-hub gene networks and identification of target drugs to reveal potential molecular mechanisms and therapeutic strategies. Animal models of doxorubicin-induced cardiotoxicity were constructed to validate differences in gene expression for autophagy-related signatures.

Results: PBMC and heart samples from the GSE37260 dataset were selected for analysis. There were 995 and 2357 DEGs in PBMC and heart samples, respectively, and they had 23 intersecting genes with autophagy-related genes. RT-qPCR confirmed the differential expression of 23 intersecting genes in doxorubicin-induced cardiotoxicity animal models in general agreement with the bioinformatics results. An autophagy-related signatures consisting of 23 intersecting genes is involved in mediating processes and pathways such as Autophagy, oxidative stress, Apoptosis, protein ubiquitination and phosphorylation. Moreover, Akt1, Hif1a and Mapk3 are hub genes in autophagy-associated signatures and their upstream miRNAs are mainly rno-miR-1188-5p, rno-miR-150-3p and rno-miR-326-3p, and their drugs are mainly CHEMBL55802, Carboxyamidotriazole and 3-methyladenine.

Conclusion: This study identifies for the first-time autophagy-related signatures in doxorubicin's cardiotoxicity, which could provide potential molecular mechanisms and therapeutic strategies for doxorubicin-induced cardiotoxicity.

Keywords

Autophagy; Biomarker; Cardiotoxicity; Doxorubicin; Drug target.

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