ORIGINAL RESEARCH article
Front. Cardiovasc. Med.
Sec. Atherosclerosis and Vascular Medicine
This article is part of the Research TopicCardiovascular calcification: disease mechanisms, clinical phenotypes and therapeutic strategiesView all 13 articles
Integrated Multi-Omics Analysis Reveals Key Hub Genes and Mechanisms in Calcific Aortic Stenosis
Provisionally accepted
Fengxia Wang1
Shuai Liu1
Hao-Qiang Guo2
Jiaqing Yu1Jun Cui1Qi Cheng1Nilupaer • Aisikeer1Fen Liu1Ming-Jun Duan1
Yitong Ma1*
Xiang Xie1*- 1The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- 2Xinjiang Medical University, Urumqi, China
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Objective: Aortic stenosis (AS) is a critical risk factor for the development of structural heart disease, and identifying its pathogenic genes will provide new insights into cardiac pathology and treatment. Methods: "edgeR" was used to calculate differentially expressed genes (DEGs) for bulk-RNAseq. GO, KEGG, and GSEA analyses were performed on the DEGs. Aortic valves from 8 AS patients and 8 non-AS patients were collected for proteomic sequencing. After DEG analysis, five algorithms were used to identify hub genes. ROC curves were constructed for the hub genes. Single-cell RNA sequencing (scRNAseq) was applied to systematically elaborate the mechanism in AS pathogenesis. Results: Transcriptome data showed that AS was accompanied by high expression of genes such as MMP9, CXCL8, and SPP1, with significant activation of hypoxia, inflammatory response, and fibrosis. Proteomic sequencing of calcified AS revealed significantly enhanced hypoxic response, TNF-α signaling, and extracellular matrix (ECM) formation. Sixteen hub genes, including ITGB3, ITGAV, and MMP9, were identified by five algorithms, all with high diagnostic efficacy (AUC>0.75). PCR experiments confirmed that MMP9 and PLAU were highly expressed in calcified aortic valves (P<0.05). scRNAseq revealed that in highly calcified regions, MMP9 and PLAU were mainly distributed in endothelial cells, monocytes, and macrophages, participating in the differentiation of monocytes and macrophages and relating to lipid metabolism and proinflammatory responses. Conclusion: The 16 hub genes can assist in the diagnosis of aortic stenosis, and MMP9 and PLAU may participate in AS development by regulating the proinflammatory effects of monocytes and macrophages.
Keywords: aortic stenosis, calcification, Transcriptome, Proteome, Single-cell transcriptomics
Received: 03 Jun 2025; Accepted: 24 Oct 2025.
Copyright: © 2025 Wang, Liu, Guo, Yu, Cui, Cheng, Aisikeer, Liu, Duan, Ma and Xie. 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:
Yitong Ma, myt-xj@163.com
Xiang Xie, xiangxie999@sina.com
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