title: c-Jun N-terminal kinase-mediated stabilization of microsomal prostaglandin E2 synthase-1 mRNA regulates delayed microsomal prostaglandin E2 synthase-1 expression and prostaglandin E2 biosynthesis by cardiomyocytes.
abstract: Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE(2), a key proinflammatory mediator. The purpose of this study was to elucidate the regulation of mPGES-1 mRNA expression in cardiomyocytes, define the role of JNK enzymes in this process, and characterize the role of mPGES-1 in cardiomyocyte PGE(2) biosynthesis. In neonatal cardiomyocytes, interleukin-1beta and lipopolysaccharide (LPS) both stimulated mPGES-1 mRNA expression and increased mPGES-1 mRNA stability and protein synthesis but failed to increase mPGES-1 mRNA transcription. Treatment with the JNK1/2 inhibitor, SP600125, abrogated the increases in mPGES-1 mRNA stability, mPGES-1 protein synthesis, and PGE(2) release induced by interleukin-1beta or LPS. mPGES-1 protein synthesis was observed in LPS-stimulated neonatal cardiomyocytes from jnk1(-/-) or jnk2(-/-) mice. In contrast, infection of jnk1(-/-) cardiomyocytes with an adenovirus encoding phosphorylation-resistant JNK2 (ad-JNK2-DN), or of jnk2(-/-) cardiomyocytes with ad-JNK1-DN, significantly decreased LPS-stimulated mPGES-1 protein synthesis. Similarly, co-infection with ad-JNK1-DN and ad-JNK2-DN attenuated LPS-stimulated mPGES-1 protein synthesis in cardiomyocytes from wild type mice. Targeted deletion of the gene encoding mPGES-1 led to a 3.2-fold decrease in LPS-stimulated PGE(2) release by cardiomyocytes in comparison with wild type cells but had no effect on COX-1, COX-2, mPGES-2, or cytosolic PGES mRNA levels. These studies provide direct evidence that mPGES-1 mRNA levels in cardiomyocytes are augmented by stabilization of mPGES-1 mRNA, that JNK1 or JNK2 can participate in the regulation of mPGES-1 protein synthesis in these cells, and that mPGES-1 catalyzes the majority of LPS-induced PGE(2) biosynthesis by cardiomyocytes.
authors.affiliation: Divisions of Vascular Surgery and Cardiac Surgery, Toronto General Hospital Research Institute of the University Health Network, University of Toronto, Toronto, Ontario M5G-2C4, Canada.
authors.forename: Norbert
authors.initials: N
authors.lastname: Degousee
authors.forename: Denis
authors.initials: D
authors.lastname: Angoulvant
authors.forename: Shafie
authors.initials: S
authors.lastname: Fazel
authors.forename: Eva
authors.initials: E
authors.lastname: Stefanski
authors.forename: Sipra
authors.initials: S
authors.lastname: Saha
authors.forename: Karina
authors.initials: K
authors.lastname: Iliescu
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lindsay
authors.forename: Jason E
authors.initials: JE
authors.lastname: Fish
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Audoly
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Barry B
authors.initials: BB
authors.lastname: Rubin
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D007249:Inflammation; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D000071876:Prostaglandin-E Synthases; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003609:Dactinomycin; D048031:JNK Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C000605866:Ptges2 protein, mouse