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J. Biol. Chem., Vol. 282, Issue 49, 35564-35573, December 7, 2007

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TNFR1 and TNFR2 Signaling Interplay in Cardiac Myocytes^*

Nicole Defer, Anie Azroyan, Françoise Pecker, and Catherine Pavoine¹

From the INSERM, Unité 841, Institut Mondor de Recherche Biomedicale, Equipe 19, Créteil, F-94010 and the University of Paris XII-Val de Marne, Créteil, F-94010, France

Tumor necrosis factor (TNF) plays a major role in chronic heart failure, signaling through two different receptor subtypes, TNFR1 and TNFR2. Our aim was to further delineate the functional role and signaling pathways related to TNFR1 and TNFR2 in cardiac myocytes. In cardiac myocytes isolated from control rats, TNF induced ROS production, exerted a dual positive and negative action on [Ca²⁺] transient and cell fractional shortening, and altered cell survival. Neutralizing anti-TNFR2 antibodies exacerbated TNF responses on ROS production and cell death, arguing for a major protective role of the TNFR2 pathway. Treatment with either neutralizing anti-TNFR1 antibodies or the glutathione precursor, N-acetylcysteine (NAC), favored the emergence of TNFR2 signaling that mediated a positive effect of TNF on [Ca²⁺] transient and cell fractional shortening. The positive effect of TNF relied on TNFR2-dependent activation of the cPLA₂ activity, independently of serine 505 phosphorylation of the enzyme. Together with cPLA₂ redistribution and AA release, TNF induced a time-dependent phosphorylation of ERK, MSK1, PKC, CaMKII, and phospholamban on the threonine 17 residue. Taken together, our results characterized a TNFR2-dependent signaling and illustrated the close interplay between TNFR1 and TNFR2 pathways in cardiac myocytes. Although apparently predominant, TNFR1-dependent responses were under the yoke of TNFR2, acting as a critical limiting factor. In vivo NAC treatment proved to be a unique tool to selectively neutralize TNFR1-mediated effects of TNF while releasing TNFR2 pathways.

Received for publication, May 15, 2007 , and in revised form, September 19, 2007.

^* This work was supported by grants from the Institut National de la Santéet de la Recherche Médicale, the Université Paris-Val-de Marne, and the Association Française contre les Myopathies. 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 To whom correspondence should be addressed: INSERM, Unité 841, Institut Mondor de Recherche Biomédicale, équipe 19, Hôpital Henri Mondor, Creteil, F-94010, France. Tel.: 33-1-49-81-35-34; Fax: 33-1-48-98-09-08; E-mail: catherine.pavoine{at}creteil.inserm.fr.

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