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J. Biol. Chem., Vol. 280, Issue 4, 3112-3120, January 28, 2005

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STAT-3-dependent Cytosolic Phospholipase A₂ Expression Is Required for Thrombin-induced Vascular Smooth Muscle Cell Motility^*

Nagadhara Dronadula, Zhimin Liu, Chunmei Wang, Huiqing Cao, and Gadiparthi N. Rao

From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Vascular smooth muscle cell (VSMC) migration from media to intima and its multiplication in intima is a contributing factor in the pathogenesis of atherosclerosis and restenosis after angioplasty. Previously, we have demonstrated that STAT-3-dependent cytosolic phospholipase A₂ (cPLA₂) expression is needed for VSMC motility induced by platelet-derived growth factor-BB, a receptor tyrosine kinase agonist (Neeli et al. (2005) J. Biol. Chem. 279, 46122–46128). In order to learn more about the STAT-3-cPLA₂ axis in motogenic signaling, here we have studied its role in VSMC motility in response to a G protein-coupled receptor (GPCR) agonist, thrombin. Thrombin induced VSMC motility in a dose-dependent manner with a maximum effect at 0.5 units/ml. Thrombin activated STAT-3 as measured by its tyrosine phosphorylation and translocation from the cytoplasm to the nucleus. Forced expression of a dominant negative mutant of STAT-3 reduced thrombin-induced STAT-3 tyrosine phosphorylation and its translocation from the cytoplasm to the nucleus. Thrombin stimulated STAT-3-DNA binding and reporter gene activities in VSMC, and these responses were blocked by FS3DM, a dominant negative mutant of STAT-3. FS3DM also attenuated thrombin-induced VSMC motility. Thrombin induced the expression of cPLA₂ in a time- and STAT-3-dependent manner. In addition, pharmacological inhibition of cPLA₂ blocked thrombin-induced VSMC motility. Furthermore, exogenous addition of arachidonic acid rescued thrombin-induced VSMC motility from inhibition by blockade of STAT-3 activation. Forced expression of cPLA₂ also surpassed the inhibitory effect of dominant negative STAT-3 on thrombin-induced VSMC motility. Together, these results show that thrombin-induced VSMC motility requires STAT-3-dependent induction of expression of cPLA₂.

Received for publication, August 24, 2004 , and in revised form, October 27, 2004.

^* This work was supported by National Institutes of Health Grants HL64165 and HL69908 (to G. N. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-7321; Fax: 901-448-7126; E-mail: grao{at}physio1.utmem.edu.

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