Abstract 13874: Thrombin Activatable Fibrinolysis Inhibitor Promotes Development of Chronic Thromboembolic Pulmonary Hypertension -A Possible Novel Therapeutic Target

Abstract

Background: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) still remains elusive. Methods and Results: CTEPH patients had higher plasma levels of and prevalence of SNPs of thrombin activatable fibrinolysis inhibitor (TAFI). Plasma levels of activated TAFI (aTAFI) were significantly increased in CTEPH patients (n=32) compared with controls (n=13) (8.7-fold, P<0.01). Immunostaining showed that TAFI and its linker protein thrombomodulin (TM) were strongly expressed in the distal pulmonary arteries (PA) in CTEPH patients. TAFI-deficient mice (TAFI –/– ) exposed to hypoxia showed significantly reduced right ventricular systolic pressure (RVSP), RV hypertrophy and PA remodeling compared with controls (all P<0.05, n=10 each). In contrast, TAFI-overexpressing mice (TAFI-Tg) exposed to hypoxia showed significantly augmented RVSP, RV hypertrophy and PA remodeling compared with controls (all P<0.01, n=19 each). Importantly, systemic TAFI-Tg mice (n=19) showed a significantly reduced survival under hypoxia compared with controls (n=22) (63% vs. 95%, P<0.01). Bone marrow transplantation demonstrated that the increased plasma levels of aTAFI, but not those in the bone marrow, promoted hypoxia-induced PA thrombus formation and PH (all P<0.01, n=10 each). Interestingly, liver-specific TAFI overexpression exacerbated hypoxia-induced PH compared with controls (all P<0.01, n=12 each). Plasma levels of TAFI were increased by hypoxia and were correlated with clot lysis time and the severity of PH. Morphological analysis using 3 dimensional-CT showed multiple obstruction of PAs in TAFI-Tg mice after hypoxic exposure (P<0.01, n=10 each). Mechanistic experiments demonstrated that treatment with human TAFI (300 nM) increased permeability of PA endothelial cells and proliferation of PA smooth muscle cells compared with vehicle controls (n=10 each, both P<0.01). Finally, a PPARα agonist, WY14643, significantly reduced plasma levels of TAFI, ameliorated hypoxia-induced PH and significantly improved mortality (-70%) in TAFI-Tg mice compared with controls (P<0.01, n=12 each). Conclusions: TAFI promotes PA thrombus formation and the development of PH and could be a novel biomarker and therapeutic target for the disorder.