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J. Biol. Chem., Vol. 283, Issue 18, 11964-11971, May 2, 2008

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The Role of RIP2 in p38 MAPK Activation in the Stressed Heart^*

Sebastien Jacquet, Yasuhiro Nishino, Sarawut Kumphune, Pierre Sicard, James E. Clark, Koichi S. Kobayashi, Richard A. Flavell^¶, Jan Eickhoff^||, Matt Cotten^**, and Michael S. Marber¹

From the Cardiovascular Division, King's College London, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom, the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, the ^¶Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, ^||GBC Biotech, München D82152, Germany, and ^**Medical Research Council Laboratories, P. O. Box 273, Banjul, Gambia

The activation of p38 MAPK by dual phosphorylation aggravates myocardial ischemic injury and depresses cardiac contractile function. SB203580, an ATP-competitive inhibitor of p38 MAPK and other kinases, prevents this dual phosphorylation during ischemia. Studies in non-cardiac tissue have shown receptor-interacting protein 2 (RIP2) lies upstream of p38 MAPK, is SB203580-sensitive and ischemia-responsive, and aggravates ischemic injury. We therefore examined the RIP2-p38 MAPK signaling axis in the heart. Adenovirus-driven expression of wild-type RIP2 in adult rat ventricular myocytes caused robust, SB203580-sensitive dual phosphorylation of p38 MAPK associated with activation of p38 MAPK kinases MKK3, MKK4, and MKK6. The effect of SB203580 was recapitulated by unrelated inhibitors of RIP2 or the downstream MAPK kinase kinase, TAK1. However, overexpression of wild-type, kinase-dead, caspase recruitment domain-deleted, or kinase-dead and caspase recruitment domain-deleted forms of RIP2 had no effect on the activating dual phosphorylation of p38 MAPK during simulated ischemia. Similarly, p38 MAPK activation and myocardial infarction size in response to true ischemia did not differ between hearts from wild-type and RIP2 null mice. However, both p38 MAPK activation and the contractile depression caused by the endotoxin component muramyl dipeptide were attenuated by SB203580 and in RIP2 null hearts. Although RIP2 can cause myocardial p38 MAPK dual phosphorylation in the heart under some circumstances, it is not responsible for the SB203580-sensitive pattern of activation during ischemia.

Received for publication, September 14, 2007 , and in revised form, February 27, 2008.

^* This work was supported by Wellcome Trust Grant 074653 and British Heart Foundation Grant 07/073/23432 (to M. S. M.). 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. E-mail: mike.marber{at}kcl.ac.uk.

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				P. Sicard, S. Jacquet, K. S. Kobayashi, R. A. Flavell, and M. S. Marber Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1 Cardiovasc Res, July 15, 2009; 83(2): 277 - 284. [Abstract] [Full Text] [PDF]