Published online before print March 20, 2003, doi: 10.1161/01.RES.0000067929.01404.03
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Submitted on September 23, 2002
Revised on March 6, 2003
Accepted on March 11, 2003
MAP Kinase Kinase 6-p38 MAP Kinase Signaling Cascade Regulates Cyclooxygenase-2 Expression in Cardiac Myocytes In Vitro and In Vivo
Norbert Degousee ;
From the Division of Vascular Surgery (N.D., E.S., M.C., T.F.L., B.B.R.), Toronto General Hospital, Toronto, Ontario; San Diego State University Heart Institute and the Department of Biology (J.M., D.J.T., C.C.G.), San Diego State University, San Diego, Calif; and Renal Division and Department of Medicine (J.E.F., P.A.M.), St Michael's Hospital and University of Toronto, Toronto, Ontario.
* To whom correspondence should be addressed. E-mail: barry.rubin{at}uhn.on.ca.
Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38
and p38
2 MAPK mRNA in rat cardiac myocytes. Interleukin-1 induced the phosphorylation of p38 and p382 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E2 (PGE2) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p382 MAPK inhibited interleukin-1-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38 and p382 MAPK inhibitor, SB202190, attenuated interleukin-1-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p382 MAPK, in the absence of interleukin-1, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1-induced cardiac myocyte COX-2 gene expression and PGE2 biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo.
Key words: MAP kinase kinase 6 • prostaglandins • recombinant proteins • transgenic mice
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