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J. Biol. Chem., Vol. 282, Issue 5, 2918-2928, February 2, 2007

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Transglutaminase-dependent RhoA Activation and Depletion by Serotonin in Vascular Smooth Muscle Cells^*

Christophe Guilluy, Malvyne Rolli-Derkinderen¹, Pierre-Louis Tharaux^¶, Gerry Melino^||, Pierre Pacaud², and Gervaise Loirand³

From the INSERM U533 Institut du Thorax, Université de Nantes, 44322 Nantes cedex 3, France, ^¶INSERM U702, Hôpital Tenon, Paris, France, ^||Biochemistry Laboratory, University of Rome "Tor Vergata," 00133 Rome, Italy, and UMR CNRS 6214-INSERM 771, Facultéde Médecine, 49045 Angers, France

The small G protein RhoA plays a major role in several vascular processes and cardiovascular disorders. Here we analyze the mechanisms of RhoA regulation by serotonin (5-HT) in arterial smooth muscle. 5-HT (0.1–10 µM) induced activation of RhoA followed by RhoA depletion at 24–72 h. Inhibition of 5-HT1 receptors reduced the early phase of RhoA activation but had no effect on 5-HT-induced delayed RhoA activation and depletion, which were suppressed by the 5-HT transporter inhibitor fluoxetine and the transglutaminase inhibitor monodansylcadaverin and in type 2 transglutaminase-deficient smooth muscle cells. Coimmunoprecipitations demonstrated that 5-HT associated with RhoA both in vitro and in vivo. This association was calcium-dependent and inhibited by fluoxetine and monodansylcadaverin. 5-HT promotes the association of RhoA with the E3 ubiquitin ligase Smurf1, and 5-HT-induced RhoA depletion was inhibited by the proteasome inhibitor MG132 and the RhoA inhibitor Tat-C3. Simvastatin, the Rho kinase inhibitor Y-27632, small interfering RNA-mediated RhoA gene silencing, and long-term 5-HT stimulation induced Akt activation. In contrast, inhibition of 5-HT-mediated RhoA degradation by MG132 prevented 5-HT-induced Akt activation. Long-term 5-HT stimulation also led to the inhibition of the RhoA/Rho kinase component of arterial contraction. Our data provide evidence that 5-HT, internalized through the 5-HT transporter, is transamidated to RhoA by transglutaminase. Transamidation of RhoA leads to RhoA activation and enhanced proteasomal degradation, which in turn is responsible for Akt activation and contraction inhibition. The observation of transamidation of 5-HT to RhoA in pulmonary artery of hypoxic rats suggests that this process could participate in pulmonary artery remodeling and hypertension.

Received for publication, May 2, 2006 , and in revised form, November 9, 2006.

^* This work was supported by grants from the INSERM, the Agence Nationale de la Recherche, and the Fondation pour la Recherche Médicale. 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.

¹ Supported by a grant from Groupe de Réflexion sur la Recherche Cardiovasculaire.

² To whom correspondence may be addressed: Inserm U-533, Faculté des Sciences, 2 rue de la Houssinière, BP 92208, 44322 Nantes cedex 3, France. Tel./Fax: 33-2-51-12-56-14; E-mail: pierre.pacaud{at}univ-nantes.fr. ³ To whom correspondence may be addressed: Inserm U-533, Faculté des Sciences, 2 rue de la Houssinière, BP 92208, 44322 Nantes cedex 3, France. Tel./Fax: 33-2-51-12-56-14; E-mail: gervaise.loirand{at}univ-nantes.fr.

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