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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 8, 2007; DOI: 10.1124/jpet.106.118042

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Received for publication December 1, 2006.
Revised March 6, 2007.
Accepted for publication March 7, 2007.

Protein kinase A inhibits lysophosphatidic acid-induced migration of airway smooth muscle cells

Masakazu Hirakawa 1, Yuji Karashima 1, Michi Watanabe 1, Chiwaka Kimura 1, Yushi Ito 1, Masahiro Oike 1*

1 Kyushu University, Graduate School of Medical Sciences

* Address correspondence to: E-mail: moike{at}pharmaco.med.kyushu-u.ac.jp

Abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid that is released from activated platelets, and affects contractile properties of airway smooth muscle cells. However, possible roles of LPA on cell migration, one of the initial events of airway remodeling, are not clarified. This study aimed to examine the effects of LPA on migration and actin fiber formation in bovine tracheal smooth muscle cells (BTSMCs). Random and oriented cell migrations were examined with wound assay and Boyden chamber assay, respectively. Cytosolic actin fibers were stained with rhodamine-phalloidin. Membrane translocation of RhoA, a hallmark of RhoA activation, was assessed by Western blotting. LPA augmented the migration of BTSMCs from wounded confluent monolayer, but did not accelerate the chemotactic migration toward LPA. LPA also induced a transient actin reorganization and RhoA activation. Dense actin fibers were observed mainly in the wound edge but not in migrated cells, thereby suggesting the role of actin reorganization in the initiation of cell migration. LPA-induced actin fiber formation was blocked by Y27632, an inhibitor of Rho-kinase. Effects of LPA on migration and actin fiber formation were also inhibited by cAMP-elevating agents, i.e., dibutyryl cAMP, forskolin, isoproterenol and theophylline. KT5720, a protein kinase A (PKA) inhibitor, reversed the inhibitory actins of cAMP on LPA-induced responses. These results indicate that LPA induces cAMP/PKA-sensitive, RhoA-mediated random migration of BTSMCs. Regulation of this mechanism would be beneficial for the control of airway remodelling.


Key words: actin cytoskeleton, airway remodelling, airway smooth muscle, lysophosphatidic acid, migration, protein kinase A


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