PAR2 is a G-protein–coupled receptor activated by serine proteases such as factor Xa. While implicated in cardiovascular pathology, its specific role in HF pathogenesis remains undefined. We aim to investigate the biological, clinical, and genetic relevance of protease-activated receptor 2 (PAR2, encoded by F2RL1) in heart failure (HF), and evaluate its potential for personalized risk stratification and therapeutic targeting.
We analyzed myocardial transcriptomic data from two biopsy cohorts (n = 316 and n = 84), linking F2RL1 expression to HF-related molecular and clinical features. Co-expression and pathway enrichment analyses were conducted. Genetic associations were assessed using HERMES HF GWAS (n = 583,167) and the UK Biobank (n = 20,650). Cell culture experiments were performed in THP-1 monocytes using the PAR2 antagonist I-191 (1 µM) and the PAR2 agonist peptide SLIGKV (50 µM) for 1 hour.
F2RL1 expression correlated with NPPB (r = 0.613; FDR p = 6.8 × 10⁻³⁰) and was co-expressed with genes involved in inflammatory signaling, oxidative stress and extracellular remodeling in both non-failing and failing myocardium. Higher F2RL1 levels were associated with increased NT-proBNP (β = 3.85 × 10⁷ ± 1.2; FDR p = 0.013) and adverse left ventricular remodeling. Genetic analyses linked F2RL1 expression in monocytes and cardiovascular tissues to HF risk (r = 0.85–0.93; p < 10⁻⁴). Variant rs1529505 was a monocyte cell-specific enhancer and cis-eQTL for F2RL1, associated with increased HF-related mortality (OR = 1.16 [1.02–1.32]; p = 0.0249). PAR2 stimulation in THP-1 cells significantly increased monocyte activation, as indicated by elevated TNFA mRNA expression (p = 0.02), which was effectively inhibited by co-treatment with the PAR2 antagonist I-191 (p = 0.01).
The mechanistic link between PAR2-driven monocyte inflammation and clinical HF outcomes suggests that a common enhancer variant linked to F2RL1 expression in monocytes may serve as a biomarker for precision HF management, identifying patients who could benefit from targeted anticoagulation therapy to mitigate PAR2-mediated inflammatory pathways.
