Integrated microarray-based and single-cell transcriptomic analyses reveal cell adhesion-related fibrotic remodeling...

Heart failure (HF) is characterized by impaired cardiac pumping function and progressive remodeling. Cell adhesion is essential for tissue integrity and the regulation of inflammation and fibrosis. This study aimed to identify key cell adhesion-related genes (CARGs) and explore their roles in HF.

HF-related transcriptomic datasets (GSE1621, GSE5500, GSE36074, GSE18224, GSE308859, and GSE116250) were obtained from GEO. Differentially expressed genes were intersected with cell adhesion-related genes from MSigDB to identify CARGs. Functional enrichment and protein-protein interaction analyses were performed. A CARG-based CelladhesionScore was constructed to evaluate its discriminatory value and associated pathways. Key CARGs were identified using CytoHubba. Single-cell transcriptomic analysis was conducted to assess fibroblast states and gene dynamics. GSE36074 and a transverse aortic constriction (TAC) mouse model were used for validation by qPCR, Western blotting, and immunohistochemistry.

Forty-five differentially expressed CARGs were identified and were mainly enriched in cell adhesion, extracellular region, and ECM-receptor interaction pathways. The CelladhesionScore distinguished HF samples from controls, while the high-CelladhesionScore group showed enrichment of fibrosis-related pathways. Col5a1, Col6a1, and Fbn1 were identified as key CARGs. Single-cell analysis showed that these genes were predominantly expressed in fibroblasts and associated with fibroblast-state changes and ECM remodeling. Their upregulation was consistently validated in external datasets and the TAC mouse model.

Col5a1, Col6a1, and Fbn1 are key CARGs associated with HF and fibroblast-mediated ECM remodeling. These findings provide new insights into cell adhesion-related molecular alterations in HF and may facilitate the identification of candidate biomarkers and therapeutic targets.