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

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 rece...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-05, Vol.283 (18), p.11964-11971
Main Authors: Jacquet, Sebastien, Nishino, Yasuhiro, Kumphune, Sarawut, Sicard, Pierre, Clark, James E., Kobayashi, Koichi S., Flavell, Richard A., Eickhoff, Jan, Cotten, Matt, Marber, Michael S.
Format: Article
Language:English
Subjects:
Acetylmuramyl-Alanyl-Isoglutamine - pharmacology
Animals
Cells, Cultured
Enzyme Activation - drug effects
Enzyme Catalysis and Regulation
Imidazoles - pharmacology
In Vitro Techniques
Male
Mice
Myocardial Contraction - drug effects
Myocardial Infarction - chemically induced
Myocardial Infarction - enzymology
Myocardial Infarction - pathology
Myocardium - enzymology
Myocardium - pathology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - enzymology
p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases - metabolism
Protein Structure, Tertiary
Pyridines - pharmacology
Pyrimidines - pharmacology
Rats
Receptor-Interacting Protein Serine-Threonine Kinase 2 - antagonists & inhibitors
Receptor-Interacting Protein Serine-Threonine Kinase 2 - chemistry
Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M707750200