TNFα and IL-1 induce IL-6 expression in human cardiac fibroblasts: Role of p38 MAP kinase subtypes

Abstract

No. 7 The role of RIP2 in p38 MAPK activation in the stressed heart S. Jacquet⁎, Y. Nishino, S. Kumphune, P. Sicard, J.E. Clark, K.S. Kobayashi, R.A. Flavell, J. Eickhoff, M. Cotten, M.S. Marber. Cardiovascular Division, KCL, UK ⁎ Corresponding author. Department of Cardiology, Kings College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK. Tel.: +44 20 7188 8349; fax: +44 20 7188 0970. E-mail address: sebastien.jacquet@kcl.ac.uk 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 that Receptor Interacting Protein 2 (RIP2) lies upstream of p38 MAPK, is SB203580-sensitive, ischemia-responsive and aggravates ischemic injury. We therefore examined the RIP2– p38 MAPK signaling axis in the heart. Adenoviral-driven expression of wild type RIP2 in adult rat ventricular myocytes caused robust, SB203580-sensitive, dual phosphorylation of p38 MAPK associated with activation of the p38 MAPK kinases, MKKs 3, 4 and 6. The effect of SB203580 was recapitulated by unrelated inhibitors of RIP2 or the downstream MKKK, TAK1. However, overexpression of wild type, kinase dead, CARD-deleted or kinase dead and CARD-deleted, forms ofRIP2 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 the p38 MAPK activation and the contractile depression caused by the endotoxin component muramyl dipeptide were attenuated 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.