{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:53:47Z","timestamp":1792788827685,"version":"4.5.0"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Project of Shunde Hospital of Guangzhou University of Chinese Medicine in 2025","award":["YNZX2025007"],"award-info":[{"award-number":["YNZX2025007"]}],"id":[{"id":"https:\/\/ror.org\/03qb7bg95","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Guangdong Provincial Laboratory of Traditional Chinese Medicine Project","award":["HQL2024PZ028"],"award-info":[{"award-number":["HQL2024PZ028"]}]},{"name":"Guangdong Special Support Program for Leading Talents Project","award":["0820250113"],"award-info":[{"award-number":["0820250113"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation Project","award":["2026A1515012068"],"award-info":[{"award-number":["2026A1515012068"]}]},{"name":"Guangdong Provincial Administration of Traditional Chinese Medicine Scientific Research Project on Traditional Chinese Medicine","award":["20254021"],"award-info":[{"award-number":["20254021"]}]},{"name":"National Key Laboratory of Traditional Chinese Medicine Syndrome","award":["09005651007"],"award-info":[{"award-number":["09005651007"]}]},{"name":"Foundation Strengthening Project of Guangzhou University of Chinese Medicine","award":["GZY2025GB0109"],"award-info":[{"award-number":["GZY2025GB0109"]}],"id":[{"id":"https:\/\/ror.org\/03qb7bg95","id-type":"ROR","asserted-by":"crossref"}]},{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome","award":["SKLKY2024B0002"],"award-info":[{"award-number":["SKLKY2024B0002"]}]},{"name":"Guangdong Provincial National Comprehensive Reform Demonstration Zone for Traditional Chinese Medicine Science and Technology Co-construction Project","award":["GZY-KJS-GD-2025-012"],"award-info":[{"award-number":["GZY-KJS-GD-2025-012"]}]},{"name":"The 2025 National Comprehensive Reform Demonstration Zone for Traditional Chinese Medicine Science and Technology Co-construction Project","award":["GZY-KJS-GD-2025-058"],"award-info":[{"award-number":["GZY-KJS-GD-2025-058"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>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 potentially involved in VA-HF synergy using integrative computational approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2009=\u200916,243). 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\u2019s trichrome staining, and vascular aging markers (P16, P21) by qPCR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u2009=\u20090.978). 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 (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05). 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 suggest that these genes may play important roles in VA-HF comorbidity (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0357886","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T17:45:28Z","timestamp":1789494328000},"page":"e0357886","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["HMOX2-driven crosstalk between vascular aging and heart failure: A multimodal bioinformatics and explainable machine learning approach with experimental validation"],"prefix":"10.1371","volume":"21","author":[{"given":"Jinze","family":"Li","sequence":"first","affiliation":[{"name":"Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7841-3460","authenticated-orcid":true,"given":"Guiting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"The First Clinical Medical College, Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaochu","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"The First Clinical Medical College, Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixuan","family":"Song","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"The First Clinical Medical College, Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiantao","family":"Liu","sequence":"additional","affiliation":[{"name":"Shunde Hospital of Guangzhou University of Chinese Medicine","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzao","family":"Shen","sequence":"additional","affiliation":[{"name":"Shunde Hospital of Guangzhou University of Chinese Medicine","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanjin","family":"Luo","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"The First Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"The First Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, China"]},{"name":"State Key Laboratory of Traditional Chinese Medicine Syndrome","place":["Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"10","key":"pone.0357886.ref001","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/s41569-024-01046-6","article-title":"Global epidemiology of heart failure","volume":"21","author":"MS Khan","year":"2024","journal-title":"Nat Rev Cardiol"},{"issue":"8","key":"pone.0357886.ref002","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s41569-024-00997-0","article-title":"Contemporary pharmacological treatment and management of heart failure","volume":"21","author":"B Bozkurt","year":"2024","journal-title":"Nat Rev Cardiol"},{"issue":"8","key":"pone.0357886.ref003","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.jacc.2021.12.017","article-title":"Inflammation, aging, and cardiovascular disease: Jacc review topic of the week","volume":"79","author":"L Liberale","year":"2022","journal-title":"J Am Coll Cardiol"},{"issue":"1","key":"pone.0357886.ref004","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41569-022-00739-0","article-title":"Mechanisms and consequences of endothelial cell senescence","volume":"20","author":"SI Bloom","year":"2023","journal-title":"Nat Rev Cardiol"},{"issue":"8","key":"pone.0357886.ref005","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.jacc.2019.11.061","article-title":"Mechanisms of Vascular Aging, A Geroscience Perspective: JACC Focus Seminar","volume":"75","author":"Z Ungvari","year":"2020","journal-title":"J Am Coll Cardiol"},{"issue":"9","key":"pone.0357886.ref006","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1002\/ejhf.2994","article-title":"Artificial intelligence and heart failure: A state-of-the-art review","volume":"25","author":"MS Khan","year":"2023","journal-title":"Eur J Heart Fail"},{"issue":"11","key":"pone.0357886.ref007","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1161\/CIRCRESAHA.125.325637","article-title":"Aging at the Crossroads of Organ Interactions: Implications for the Heart","volume":"136","author":"I Sen","year":"2025","journal-title":"Circ Res"},{"key":"pone.0357886.ref008","doi-asserted-by":"crossref","first-page":"112890","DOI":"10.1016\/j.intimp.2024.112890","article-title":"Mechanisms of QingRe HuoXue Formula in atherosclerosis Treatment: An integrated approach using Bioinformatics, Machine Learning, and experimental validation","volume":"141","author":"G Zhou","year":"2024","journal-title":"Int Immunopharmacol"},{"issue":"29","key":"pone.0357886.ref009","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1093\/eurheartj\/ehad381","article-title":"Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice","volume":"44","author":"Y Zhang","year":"2023","journal-title":"Eur Heart J"},{"key":"pone.0357886.ref010","doi-asserted-by":"crossref","first-page":"118685","DOI":"10.1016\/j.jep.2024.118685","article-title":"Jin-Xin-Kang alleviates heart failure by mitigating mitochondrial dysfunction through the Calcineurin\/Dynamin-Related Protein 1 signaling pathway","volume":"335","author":"L Lin","year":"2024","journal-title":"J Ethnopharmacol"},{"issue":"7","key":"pone.0357886.ref011","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2024.e28446","article-title":"Screening for immune-related biomarkers associated with myasthenia gravis and dilated cardiomyopathy based on bioinformatics analysis and machine learning","volume":"10","author":"G Zhou","year":"2024","journal-title":"Heliyon"},{"issue":"6","key":"pone.0357886.ref012","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1161\/CIRCRESAHA.121.319815","article-title":"Endothelial Senescence: A New Age in Pulmonary Hypertension","volume":"130","author":"MK Culley","year":"2022","journal-title":"Circ Res"},{"issue":"18","key":"pone.0357886.ref013","doi-asserted-by":"crossref","first-page":"4833","DOI":"10.1016\/j.cell.2024.07.012","article-title":"A systems view of the vascular endothelium in health and disease","volume":"187","author":"HG Augustin","year":"2024","journal-title":"Cell"},{"key":"pone.0357886.ref014","doi-asserted-by":"crossref","first-page":"112834","DOI":"10.1016\/j.intimp.2024.112834","article-title":"Huanglian Jiedu Decoction enhances the stability of atherosclerotic plaques through SLC2A1-mediated efferocytosis","volume":"140","author":"G Zhou","year":"2024","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"pone.0357886.ref015","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41572-024-00540-y","article-title":"Heart failure with preserved ejection fraction","volume":"10","author":"CE Hamo","year":"2024","journal-title":"Nat Rev Dis Primers"},{"issue":"9","key":"pone.0357886.ref016","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41569-020-0363-2","article-title":"Evaluation and management of heart failure with preserved ejection fraction","volume":"17","author":"BA Borlaug","year":"2020","journal-title":"Nat Rev Cardiol"},{"key":"pone.0357886.ref017","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev-med-042220-022745","article-title":"Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies","volume":"73","author":"K Omote","year":"2022","journal-title":"Annu Rev Med"},{"issue":"22","key":"pone.0357886.ref018","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1001\/jama.2024.5596","article-title":"Prognostic Value of Cardiovascular Biomarkers in the Population","volume":"331","author":"JT Neumann","year":"2024","journal-title":"JAMA"},{"issue":"8","key":"pone.0357886.ref019","article-title":"Exosome Release Delays Senescence by Disposing of Obsolete Biomolecules","volume":"10","author":"W Zou","year":"2023","journal-title":"Adv Sci (Weinh)"},{"issue":"1","key":"pone.0357886.ref020","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.1038\/s41467-022-31890-4","article-title":"Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis","volume":"13","author":"N Caporarello","year":"2022","journal-title":"Nat Commun"},{"issue":"3","key":"pone.0357886.ref021","doi-asserted-by":"crossref","first-page":"555","DOI":"10.3390\/antiox11030555","article-title":"Heme Oxygenase-1: An Anti-Inflammatory Effector in Cardiovascular, Lung, and Related Metabolic Disorders","volume":"11","author":"SW Ryter","year":"2022","journal-title":"Antioxidants (Basel)"},{"issue":"4","key":"pone.0357886.ref022","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1152\/physrev.00003.2016","article-title":"Heme Oxygenases in Cardiovascular Health and Disease","volume":"96","author":"A Ayer","year":"2016","journal-title":"Physiol Rev"},{"issue":"10","key":"pone.0357886.ref023","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0292990","article-title":"Loss of heme oxygenase 2 causes reduced expression of genes in cardiac muscle development and contractility and leads to cardiomyopathy in mice","volume":"18","author":"R Cetin-Atalay","year":"2023","journal-title":"PLoS One"},{"issue":"4","key":"pone.0357886.ref024","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1515\/hsz-2019-0386","article-title":"The cGMP system: components and function","volume":"401","author":"F Hofmann","year":"2020","journal-title":"Biol Chem"},{"issue":"2","key":"pone.0357886.ref025","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1161\/HYPERTENSIONAHA.124.21709","article-title":"Cardiac cGMP Regulation and Therapeutic Applications","volume":"82","author":"S Mishra","year":"2025","journal-title":"Hypertension"},{"issue":"6","key":"pone.0357886.ref026","article-title":"Identifying subtypes of heart failure from three electronic health record sources with machine learning: an external, prognostic, and genetic validation study","volume":"5","author":"A Banerjee","year":"2023","journal-title":"Lancet Digit Health"},{"issue":"9","key":"pone.0357886.ref027","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/s43587-024-00663-7","article-title":"Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice","volume":"4","author":"S Zumerle","year":"2024","journal-title":"Nat Aging"},{"key":"pone.0357886.ref028","doi-asserted-by":"crossref","first-page":"119176","DOI":"10.1016\/j.atherosclerosis.2025.119176","article-title":"Simvastatin ameliorates senescence-induced mitochondrial dysfunction in vascular smooth muscle cells","volume":"403","author":"C Rossi","year":"2025","journal-title":"Atherosclerosis"},{"issue":"22","key":"pone.0357886.ref029","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1161\/CIRCULATIONAHA.114.013777","article-title":"Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy","volume":"131","author":"D Cardinale","year":"2015","journal-title":"Circulation"},{"issue":"6","key":"pone.0357886.ref030","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.cmet.2023.02.006","article-title":"Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity","volume":"35","author":"M Ozcan","year":"2023","journal-title":"Cell Metab"},{"key":"pone.0357886.ref031","article-title":"Stiffness drives endothelial senescence and inflammation in aging and doxorubicin-induced vascular dysfunction","author":"C Romagnoli","year":"2026","journal-title":"bioRxiv"},{"issue":"5","key":"pone.0357886.ref032","doi-asserted-by":"crossref","DOI":"10.1111\/acel.70535","article-title":"Fisetin Supplementation Attenuates Premature Vascular Aging Induced by Doxorubicin via Suppression of Cellular Senescence and Mitochondrial Oxidative Stress","volume":"25","author":"MA Darrah","year":"2026","journal-title":"Aging Cell"},{"issue":"4","key":"pone.0357886.ref033","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/s41588-023-01337-7","article-title":"Dual genetic tracing reveals a unique fibroblast subpopulation modulating cardiac fibrosis","volume":"55","author":"M Han","year":"2023","journal-title":"Nat Genet"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357886","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T17:45:35Z","timestamp":1789494335000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357886"}},"subtitle":[],"editor":[{"given":"Wan-Tien","family":"Chiang","sequence":"first","affiliation":[{"name":"Augusta University","place":["TAIWAN"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0357886","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]}}}