Activated TAFI Promotes the Development of Chronic Thromboembolic Pulmonary Hypertension: A Possible Novel Therapeutic Target.

Abstract

RATIONALE:

Pulmonary hypertension is a fatal disease; however, its pathogenesis still remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) is synthesized by the liver and inhibits fibrinolysis. Plasma TAFI levels are significantly increased in chronic thromboembolic pulmonary hypertension (CTEPH) patients.

OBJECTIVE:

To determine the role of activated TAFI (TAFIa) in the development of CTEPH.

METHODS AND RESULTS:

Immunostaining showed that TAFI and its binding partner thrombomodulin (TM) were highly expressed in the pulmonary arteries (PAs) and thrombus in patients with CTEPH. Moreover, plasma levels of TAFIa were increased 10-fold in CTEPH patients compared with controls. In mice, chronic hypoxia caused a 25-fold increase in plasma levels of TAFIa with increased plasma levels of thrombin and TM, which led to thrombus formation in PA, vascular remodeling, and pulmonary hypertension. Consistently, plasma clot lysis time was positively correlated with plasma TAFIa levels in mice. Additionally, overexpression of TAFIa caused organized thrombus with multiple obstruction of PA flow and reduced survival rate under hypoxia in mice. Bone marrow transplantation showed that circulating plasma TAFI from the liver, not in the bone marrow, was activated locally in PA endothelial cells through interactions with thrombin and TM. Mechanistic experiments demonstrated that TAFIa increased PA endothelial permeability, smooth muscle cell proliferation, and monocyte/macrophage activation. Importantly, TAFIa inhibitor and peroxisome proliferator-activated receptor-α agonists significantly reduced TAFIa and ameliorated animal models of pulmonary hypertension in mice and rats.

CONCLUSIONS:

These results indicate that TAFIa could be a novel biomarker and realistic therapeutic target of CTEPH.

• Authors: Taijyu Satoh, Kimio Satoh, Nobuhiro Yaoita, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Kazuhiko Numano, Elias Al-Mamun, Mohammad Abdul Hai Siddique, Shinichiro Sunamura, Masamichi Nogi, Kota Suzuki, Satoshi Miyata, John Morser, Hiroaki Shimokawa
• Journal: Circulation research (Circ Res) Vol. 120 Issue 8 Pg. 1246-1262 (Apr 14 2017) ISSN: 1524-4571 [Electronic] United States
• PMID: 28289017 (Publication Type: Journal Article)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

• PPAR alpha
• Pyrimidines
• THBD protein, human
• Thrombomodulin
• pirinixic acid
• CPB2 protein, human
• Carboxypeptidase B2
• Cpb2 protein, mouse
• Cpb2 protein, rat
• Thrombin

Topics

• Adult
• Animals
• Arterial Pressure
• Capillary Permeability
• Carboxypeptidase B2 (deficiency, genetics, metabolism)
• Case-Control Studies
• Cell Proliferation
• Chronic Disease
• Disease Models, Animal
• Female
• Hep G2 Cells
• Humans
• Hypertension, Pulmonary (etiology, metabolism, physiopathology, prevention & control)
• Hypoxia (complications)
• Liver (drug effects, metabolism)
• Macrophage Activation
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Muscle, Smooth, Vascular (metabolism, pathology, physiopathology)
• Myocytes, Smooth Muscle (metabolism, pathology)
• PPAR alpha (agonists, metabolism)
• Pulmonary Artery (metabolism, pathology, physiopathology)
• Pyrimidines (pharmacology)
• Rats, Sprague-Dawley
• Signal Transduction
• Thrombin (metabolism)
• Thromboembolism (complications, metabolism, physiopathology, prevention & control)
• Thrombomodulin (metabolism)
• Transfection
• Up-Regulation