Abstract 11081: Crucial Role of Thrombin Activatable Fibrinolysis Inhibitor in the Pathogenesis of Chronic Thromboembolic Pulmonary Hypertension
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease; however, its pathogenesis still remains to be elucidated. We tested our hypothesis that thrombin activatable fibrinolysis inhibitor (TAFI) plays a crucial role in the pathogenesis of CTEPH as it regulates fibrinolysis, reduces plasmin production, and prolongs clot lysis time.
Methods and Results: In the lung of CTEPH patients, perivascular expression of TAFI in small pulmonary arteries (PA) was enhanced. In mice in vivo, chronic exposure to hypoxia (O2 10%, 3 weeks) caused TAFI up-regulation in the lung. We then newly developed TAFI- overexpressing mice (Tg), in which chronic hypoxia increased right ventricular systolic pressure (RVSP) and caused RV hypertrophy and PA remodeling to a greater extent than in littermate controls (all P<0.05, n=8 each). Moreover, Tg mice (n=19) showed a significantly reduced long-term survival under hypoxia compared with controls (n=22) (63 vs. 95%, P<0.01). To evaluate the role of TAFI for inflammatory cell recruitment, we performed bone marrow reconstitution with GFP+ cells, which demonstrated increased recruitment of GFP+ cells in Tg mice compared with controls by 3D imaging. In experiments with pulmonary artery smooth muscle cells (Tg-PASMCs) in vitro, cell proliferation was significantly increased in Tg-PASMCs compared with controls (2.8 vs. 1.8-fold, n=8 each, P<0.01). Hypoxia (2% O2) significantly increased TAFI expression and secretion from PASMCs. Furthermore, Tg-PASMCs showed significantly enhanced p38 activity and secretion of inflammatory cytokines/chemokines and growth factors compared with controls. Conditioned medium from Tg-PASMCs promoted cell proliferation compared with controls (1.3- vs. 1.1-fold, n=8 each, P<0.05). Human recombinant TAFI (100 nM) also promoted proliferation of PASMCs from CTEPH patients compared with vehicle controls (1.21- vs. 0.97-fold, n=8 each, P<0.01). Finally, plasma levels of activated TAFI were significantly increased in CTEPH patients (n=32) compared with healthy controls (n=13) (8.7-fold, P<0.01).
Conclusions: These results indicate that TAFI plays a crucial role in the pathogenesis of CTEPH, suggesting that it is a novel therapeutic target for CTEPH.
Author Disclosures: T. Satoh: None. K. Satoh: None. N. Yaoita: None. N. Kikuchi: None. J. Omura: None. R. Kurosawa: None. M. Nogi: None. T. Otsuki: None. K. Kozu: None. K. Numano: None. K. Suzuki: None. S. Sunamura: None. S. Tatebe: None. T. Aoki: None. K. Sugimura: None. H. Shimokawa: None.
- © 2015 by American Heart Association, Inc.