Protective role of protein C inhibitor in monocrotaline‐induced pulmonary hypertension

• Published in: Journal of thrombosis and haemostasis Vol. 4; no. 11; pp. 2331 - 2339
• Main Authors: NISHII, Y., GABAZZA, E.C., FUJIMOTO, H., NAKAHARA, H., TAKAGI, T., BRUNO, N., D'ALESSANDRO‐GABAZZA, C. N., MARUYAMA, J., MARUYAMA, K., HAYASHI, T., ADACHI, Y., SUZUKI, K., TAGUCHI, O.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2006
• Subjects: Animals; Bronchoalveolar Lavage Fluid; coagulation; fibrinolysis; Humans; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - prevention & control; Intercellular Signaling Peptides and Proteins - metabolism; Lung - metabolism; Lung - pathology; Mice; Mice, Transgenic; Monocrotaline - pharmacology; Monocrotaline - toxicity; Protein C Inhibitor - genetics; Protein C Inhibitor - metabolism; Protein C Inhibitor - therapeutic use; protein C pathway; pulmonary hypertension; Thrombin - metabolism
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2006.02174.x

Background: Protein C inhibitor (PCI) plays a role in multiple biological processes including fertilization, coagulation, fibrinolysis and kinin systems. Objectives: We hypothesized that PCI participates in the pathogenesis of pulmonary hypertension. To demonstrate this, we compared the development of pulmonary hypertension in mice overexpressing PCI in the lung with wild‐type (WT) mice. Pulmonary hypertension was induced by s.c. injection of 600 mg kg−1 of monocrotaline weekly for 8 weeks. Results: Right ventricular arterial pressure was significantly increased in monocrotaline‐treated WT mice compared with that in monocrotaline‐treated transgenic mice. Bronchoalveolar lavage fluid (BALF) levels of thrombin–antithrombin complex, monocyte chemoattractant protein‐1 and platelet‐derived growth factor, and the plasma level of tumor necrosis factor‐α were significantly increased in monocrotaline‐treated WT mice as compared with monocrotaline‐treated PCI transgenic mice. Increased level of PCI‐thrombin complex was detected in BALF from monocrotaline‐treated PCI transgenic mice as compared with saline‐treated PCI transgenic mice. Conclusions: This study showed that increased expression of PCI in the lung is protective against monocrotaline‐induced pulmonary hypertension, suggesting a potential beneficial effect of PCI for the therapy of this disease.