Identification and exploration of aging‐related subtypes and distinctive role of SERPINE1 in heart failure based on single‐cell and bulk RNA sequencing data

Abstract Aging is a major risk factor for heart failure (HF) and is the leading cause of death worldwide. Currently, the nature of the relationship between aging and HF is not entirely clear. Herein, this study aimed to explore new diagnostic biomarkers, molecular typing and therapeutic strategies for HF by investigating the biological significance of aging‐related genes in HF. A total of 157 differentially expressed genes (DEGs) were screened totally between HF and normal samples, and functional enrichment analysis of DEGs revealed the strong association of HF progression with aging, immune processes and metabolism. Six HF‐specific aging‐related genes were further identified, and a diagnostic model was developed and validated for good diagnostic efficacy. In addition, we collected blood samples from 10 normal controls and 10 HF patients for RT‐qPCR analysis to verify the bioinformation. We also identified two aging‐associated subtypes with distinctly different immune infiltration and metabolic microenvironment. Further single‐cell sequencing analysis conducted in the study identified SERPINE1 as a key gene in HF. The distinctive role of SERPINE1 fibroblasts was revealed, including three main findings: (I) fibroblasts had a higher proportion and expression of SERPINE1 levels in HF; (II) the ligand–receptor pair MDK‐LRP1 made the most contributions in high interactions with other cell types in SERPINE1 fibroblasts; and (III) SERPINE1 fibroblasts were associated with the interaction of extracellular matrix and receptor and may be regulated by the transcription factor EGR1. In conclusion, this study highlights the importance of aging‐related genes in diagnosing HF and regulating immune infiltration. We also identified different HF subtypes and a potentially crucial gene, which may provide a better understanding of the molecular‐level mechanisms of aging‐related HF and aid in developing effective therapeutic strategies.