ORIGINAL RESEARCH article
Front. Aging
Sec. Genetics, Genomics and Epigenomics of Aging
HMOX2-Driven Crosstalk Between Vascular Aging and Heart Failure: A Multi-Modal Bioinformatics and Explainable Machine Learning Approach
Provisionally accepted
- Guangzhou University of Chinese Medicine, Guangzhou, China
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Purpose: The molecular mechanisms linking vascular aging (VA) and heart failure (HF) remain elusive, hindering therapeutic strategies for their comorbidity. This study aimed to identify key biomarkers and pathways driving VA-HF synergy using integrative computational approaches. Methods: We analyzed the GSE57338 dataset (136 controls, 177 HF samples) to identify HF-associated differentially expressed genes (DEGs) and constructed a weighted gene co-expression network (WGCNA). Vascular aging-related targets were retrieved from GeneCards (n=16,243). Consensus genes (CGs) were derived by intersecting DEGs, WGCNA hub genes, and VA-related targets. Functional enrichment, machine learning prioritization (LASSO regression, Random Forest, and SHAP-XGBoost), and network analysis (GeneMANIA) were applied to identify potential regulators. Top candidates were experimentally validated using qPCR in doxorubicin-induced rat primary vascular smooth muscle cells and human VSMC cell line for the VA model, and H9C2 cardiomyoblast injury model for HF. Further validation was performed in a mouse model of doxorubicin-induced HF, assessing cardiac function by echocardiography, myocardial fibrosis by Masson's trichrome staining, and vascular senescence markers (P16, P21) by qPCR. Results: We identified 272 CGs enriched in cGMP-PKG signaling, cytoskeletal regulation, and PPAR pathways. Machine learning prioritized 12 core genes, with HMOX2 as the top predictor (AUC=0.978). qPCR analysis confirmed upregulation of HMOX2, S1PR3, and SERPINA3 in doxorubicin-treated rat primary vascular smooth muscle cells, human VSMC cell line, and H9C2 cardiomyoblasts compared to controls (P < 0.05). In the mouse model, doxorubicin administration induced significant cardiac dysfunction and myocardial fibrosis, accompanied by elevated expression of senescence markers P16 and P21 in vascular tissues. These findings collectively demonstrate the key role of these genes in VA-HF comorbidity(P<0.05).
Keywords: Vascular aging, Heart Failure, HMOX2, Explainable Machine Learning, Shapley additive explanations
Received: 07 Jul 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Li, Zhou, Song, Luo and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Guiting Zhou, dreansky.lianyu@qq.com
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