Contribution of macrophage migration inhibitory factor to extracellular signal-regulated kinase activation by oxidative stress in cardiomyocytes.
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.
Fukuzawa
Jun
J
First Department of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigaoka-Higashi, Japan. fukuzawa@asahikawa-med.ac.jp
Nishihira
Jun
J
Hasebe
Naoyuki
N
Haneda
Takashi
T
Osaki
Junzo
J
Saito
Tetsuya
T
Nomura
Tomoaki
T
Fujino
Takayuki
T
Wakamiya
Nobutaka
N
Kikuchi
Kenjiro
K
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
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