Monocyte F2RL1 signaling defines an adverse remodeling phenotype in heart failure

Background PAR2 is a G-protein–coupled receptor activated by serine proteases such as factor Xa (fXa). While implicated in cardiovascular pathology, its specific role in HF pathogenesis remains undefined. We aimed to investigate the biological, clinical, and genetic relevance of protease-activated receptor 2 (PAR2, encoded by F2RL1) in heart failure (HF). Methods We analyzed myocardial transcriptomic data from two biopsy cohorts (n = 316 and n = 84) including both non-failing and failing myocardium. Co-expression and pathway enrichment analyses were conducted. Genetic associations were assessed using HERMES HF GWAS (n = 583,167). THP-1 monocytes were stimulated with fXa or PAR2 agonist ± antagonists, after which conditioned media were collected and applied to HEK293T cells transfected with an NPPB-luciferase reporter. Findings F2RL1 expression strongly correlated with NPPB (r = 0.613; FDR p = 6.8 × 10⁻³⁰) and clustered with TGF-β and TNF-driven immune signalling, extracellular matrix remodelling, oxidative phosphorylation, lipid metabolism, coagulation, and cellular stress pathways in both non-failing and failing myocardium. Canonical markers of adverse remodelling, including NPPA and NPPB, were among the top correlated transcripts. Elevated myocardial F2RL1 levels were associated with higher circulating NT-proBNP (β = 3.85 × 10⁷ ± 1.20 × 10⁷; p = 1.85 × 10⁻³; FDR p = 1.30 × 10⁻²). On transthoracic echocardiography, F2RL1 expression was significantly associated with increased left ventricular mass (LVM: β = 8.55 × 10⁶ ± 2.89 × 10⁶; p = 4.23 × 10⁻³; FDR p = 1.48 × 10⁻²) and larger left atrial volume index (LAVI: β = 3.87 × 10⁶ ± 1.44 × 10⁶; p = 8.73 × 10⁻³; FDR p = 2.30 × 10⁻²). Genetic analyses demonstrated that HF risk variants at the F2RL1 locus were strongly correlated with genetically predicted F2RL1 expression in monocytes (r = 0.85; p = 3.3 × 10⁻⁷; n = 17), linking increased F2RL1 expression to HF susceptibility. Functionally, conditioned media from PAR2- and fXa-activated THP-1 monocytes significantly increased NFAT-dependent NPPB reporter activity in recipient cells; this effect was abrogated by PAR2 antagonism (I-191) and rivaroxaban. Interpretation F2RL1 defines a monocyte-driven thrombo-inflammatory remodeling axis in human HF, and its expression and genetically regulated variability may serve as candidate biomarkers for precision patient stratification.