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Dynasore, a Dynamin Inhibitor, Induces PAI-1 Expression in MeT-5A Human Pleural Mesothelial Cells

¹ Department of Chest Medicine, Taipei Medical University Hospital and School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; ² Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan; and ³ Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

Correspondence and requests for reprints should be addressed to George Hsiao, Ph.D., Graduate Institute of Medical Sciences and Department of Pharmacology, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. E-mail: geohsiao{at}tmu.edu.tw

Plasminogen activator inhibitor-1 (PAI-1) is a primary regulator of plasminogen activation that plays an essential role in regulating the physiological thrombotic/fibrinogenic balance. The elevation of PAI-1 expression by human pleural mesothelial cells has been reported to contribute to pleural fibrosis and pleurodesis. In this study, we examined the effects on PAI-1 expression of dynasore, a cell-permeable inhibitor of dynamin, and its mechanisms in a human pleural mesothelial cell line (MeT-5A). The results indicated that dynasore enhanced transforming growth factor (TGF)-β₁– and TNF-–induced PAI-1 protein expression in a concentration-dependent manner. Furthermore, dynasore significantly up-regulated PAI-1 protein and its messenger RNA expressions. Interestingly, Smad2/3 activation was induced by TGF-β₁ but not by dynasore. Among signaling inhibitors, a c-Jun NH₂-terminal kinase (JNK) inhibitor (SP600125) markedly attenuated dynasore-stimulated PAI-1 protein production. Consistently, dynasore strongly increased JNK phosphorylation. On the other hand, there was no enhancement effect by dynasore on TGF-β₁–induced matrix metalloproteinase-2 activation. These findings suggest that dynasore may stimulate PAI-1 protein expression and enhance TGF-β₁ activity through activation of JNK-mediated signaling in human pleural mesothelial cells. Given the profibrotic effect of dynasore, further in vivo studies may be conducted to evaluate its potential as a pleurodesing agent.

Key Words: dynasore • PAI-1 • TGF-β1 • JNK • MMP-2

CLINICAL RELEVANCE Dynasore, as a dynamin inhibitor, stimulates and enhances transforming growth factor-β1–induced plasminogen activator inhibitor-1 expression, and its main mechanism might be through c-Jun NH2-terminal kinase signal pathway in human MeT-5A cells. It is proposed that dynasore may be used as a potential pleurodensing agent.

 

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