IL-1β-driven SERPINE1 Upregulation is Associated with CAD-ICM-related Cardiomyocyte Remodeling

INTRODUCTION: Coronary artery disease (CAD) may progress to ischemic cardiomyopathy (ICM) and heart failure through maladaptive cardiomyocyte remodeling and myocardial fibrosis. This study aimed to identify key molecular mediators linking inflammatory and fibrotic signaling during this pathological transition. METHODS: Single-cell RNA sequencing data from human ventricular tissues, including 2 CAD, 3 ICM, and 3 healthy samples (12,818 cells; 7 cell clusters), were integrated for analysis. Cell-cell communication and pseudotime trajectory analyses were performed. Findings were further validated using a bulk transcriptomic dataset (GSE57338), a left anterior descending artery ligation mouse model, and in vitro experiments in AC16 cardiomyocytes. RESULTS: Cardiomyocyte trajectory analysis revealed a progressive upregulation of SERPINE1 from CAD to ICM, accompanied by an expansion of SERPINE1+ cardiomyocytes enriched in inflammation- related pathways. Bulk transcriptomic data and in vivo experiments confirmed increased SERPINE1 expression in diseased myocardium. In vitro, IL-1β stimulation increased SERPINE1 expression and secretion while reducing p-SMAD2 levels. Isoproterenol (ISO) stimulation concurrently did not significantly alter SERPINE1 and SMAD2/p-SMAD2. Cardiomyocyte-specific SERPINE1 knockdown in mice partially reversed ISO-induced upregulation of fibrotic/ECM genes (Postn, Col1a1, Col3a1, Acta2), confirming its functional role in vivo. DISCUSSION: These findings indicate that SERPINE1 is associated with inflammatory signaling during disease progression and may be regulated through mechanisms that are not fully aligned with canonical TGF-β signaling. CONCLUSION: SERPINE1 is dynamically regulated during CAD-to-ICM progression and may serve as a marker of disease progression. Its dissociation from canonical TGF-β signaling suggests a potential role for inflammation-related mechanisms in its regulation and in fibrotic remodeling.