title: Contribution of macrophage migration inhibitory factor to extracellular signal-regulated kinase activation by oxidative stress in cardiomyocytes.
abstract: In response to oxidative stress, the pathogenesis of a number of cardiovascular events and several genes are stimulated by extracellular signal-regulated kinases (ERK1/2). Biphasic (early, 10 min; and delayed, 120 min) ERK1/2 activation by H(2)O(2), a reactive oxygen species, was observed in cultured neonatal rat cardiomyocytes. We investigated the hypothesis that the delayed activation of ERK1/2 depends on a factor secreted by oxidative stress (FSO). The delayed activation was inhibited by calphostin C, a protein kinase C inhibitor. Conditioned medium (CM) obtained from cells stimulated with H(2)O(2) induced rapid and monophasic ERK1/2 activation, which was not inhibited by calphostin C. In contrast, calphostin C-pretreated CM did not activate ERK1/2. Macrophage migration inhibitory factor (MIF) was one of the candidate FSOs activating ERK1/2. The existence of MIF in CM, the recombinant MIF-stimulated ERK1/2 rapid activation, and anti-MIF neutralizing antibody-induced inhibition of the delayed activation implied that MIF could be the FSO. Pretreatment of cardiomyocytes with a mitogen-activated protein kinase/ERK kinase (MEK) inhibitor did not suppress the MIF secretion, although it prevented the ERK1/2 activation by H(2)O(2). These results indicate that MIF is secreted from cardiomyocytes as a result of oxidative stress and activates ERK1/2 through a MEK1/2-dependent mechanism, although the secretion is not regulated by ERK1/2 but by protein kinase C.
authors.affiliation: First Department of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigaoka-Higashi, Japan. fukuzawa@asahikawa-med.ac.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Fukuzawa
authors.forename: Jun
authors.initials: J
authors.lastname: Nishihira
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hasebe
authors.forename: Takashi
authors.initials: T
authors.lastname: Haneda
authors.forename: Junzo
authors.initials: J
authors.lastname: Osaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Saito
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nomura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujino
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Wakamiya
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017077:Culture Media, Conditioned; D008263:Macrophage Migration-Inhibitory Factors; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases