MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo

Norbert Degousee, Joshua Martindale, Eva Stefanski, Martin Cieslak, Thomas F. Lindsay, Jason E. Fish, Philip A. Marsden, Donna J. Thuerauf, Christopher C. Glembotski, Barry B. Rubin

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

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 p38α and p38β2 MAPK mRNA in rat cardiac myocytes. Interleukin-1β induced the phosphorylation of p38α and p38β2 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 p38β2 MAPK inhibited interleukin-1β-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38α and p38β2 MAPK inhibitor, SB202190, attenuated interleukin-1β-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p38β2 MAPK, in the absence of interleukin-1β, 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-1β-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.

Original languageEnglish (US)
Pages (from-to)757-764
Number of pages8
JournalCirculation research
Volume92
Issue number7
DOIs
StatePublished - Apr 18 2003
Externally publishedYes

Keywords

  • MAP kinase kinase 6
  • Prostaglandins
  • Recombinant proteins
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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