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J. Biol. Chem., Vol. 281, Issue 23, 16058-16067, June 9, 2006

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Nitric Oxide Signaling via Nuclearized Endothelial Nitric-oxide Synthase Modulates Expression of the Immediate Early Genes iNOS and mPGES-1^*

Fernand Gobeil, Jr.¹, Tang Zhu, Sonia Brault, Antoinette Geha, Alejandro Vazquez-Tello, Audrey Fortier, David Barbaz, Daniella Checchin, Xin Hou, Moni Nader^¶, Ghassan Bkaily^¶, Jean-Philippe Gratton^||, Nikolaus Heveker, Alfredo Ribeiro-da-Silva^**, Krishna Peri, Harry Bard, Alzbeta Chorvatova, Pedro D'Orléans-Juste, Edward J. Goetzl, and Sylvain Chemtob²

From the Department of Pharmacology, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada, Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Sainte-Justine, Montréal, Québec H3T 1C5, Canada, ^¶Department of Anatomy and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada, ^||Institut de Recherches Cliniques de Montréal, Québec H2W 1R7, Canada, ^**Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada, Theratechnologies, Montréal, Québec H4S 2A4, Canada, and Department of Medicine and Microbiology-Immunology, University of California, San Francisco, California 94143-0711

Stimulation of freshly isolated rat hepatocytes with lysophosphatidic acid (LPA) resulted in LPA₁ receptor-mediated and nitricoxide-dependent up-regulation of the immediate early genes iNOS (inducible nitric-oxide synthase (NOS)) and mPGES-1 (microsomal prostaglandin E synthase-1). Because LPA is a ligand for both cell surface and intracellular receptor sites and a potent endothelial NOS (eNOS) activator, we hypothesized that NO derived from activated nuclearized eNOS might participate in gene regulation. Herein we show, by confocal microscopy performed on porcine cerebral endothelial cells expressing native LPA₁-receptor and eNOS and on HTC4 rat hepatoma cells co-transfected with recombinant human LPA₁-receptor and fused eNOS-GFP cDNA, a dynamic eNOS translocation from peripheral to nuclear regions upon stimulation with LPA. Nuclear localization of eNOS and its downstream effector, soluble guanylate cyclase, were demonstrated in situ in rat liver specimens by immunogold labeling using specific antibodies. Stimulation of this nuclear fraction with LPA and the NO donor sodium nitroprusside resulted, respectively, in increased production of nitrite (and eNOS phosphorylation) and cGMP; these separate responses were also correspondingly blocked by NOS inhibitor L-NAME and soluble guanylate cyclase inhibitor ODQ. In addition, sodium nitroprusside evoked a sequential increase in nuclear Ca²⁺ transients, activation of p42 MAPK, NF-B binding to DNA consensus sequence, and dependent iNOS RNA. This study describes a hitherto unrecognized molecular mechanism by which nuclear eNOS through ensuing NO modulates nuclear calcium homeostasis involved in gene transcription-associated events. Moreover, our findings strongly support the concept of the nucleus as an autonomous signaling compartment.

Received for publication, March 9, 2006

^* This study was supported in part by grants from the Canadian Institute of Health Research, the Heart and Stroke Foundation of Québec, and the March of Dimes. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Recipient of a Junior 1 scholarship from the Fonds de la Recherche en Santé du Québec and a researcher with the Canada Foundation for Innovation. To whom correspondence may be addressed. E-mail: Fernand.Gobeil{at}USherbrooke.ca. ² Recipient of a Canada Research Chair. To whom correspondence may be addressed. E-mail: sylvain.chemtob{at}umontreal.ca.

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