title: Role of phasic dynamism of p38 mitogen-activated protein kinase activation in ischemic preconditioning of the canine heart.
abstract: Although ischemic stress, including ischemic preconditioning (IP), activates p38 mitogen-activated protein kinase (MAPK), the relationship between p38 MAPK activation and the underlying cellular mechanisms of cardioprotection by IP is not verified in vivo. We examined the effects of the selective p38 MAPK inhibition on the cardioprotective effect of IP in the open-chest dogs. The coronary artery was occluded 4 times for 5 minutes, separated by 5 minutes of reperfusion (IP) followed by 90 minutes of occlusion and 6 hours of reperfusion. We infused SB203580 into the coronary artery during IP and 1 hour of reperfusion, during IP alone, and during sustained ischemia in the IP group. p38 MAPK activity markedly increased during IP but did not additionally increase at the onset of ischemia and was even attenuated at 15 minutes of sustained ischemia, and heat-shock protein (HSP) 27 was phosphorylated and translocated from cytosol to myofibril or nucleus without affecting total protein level at the onset of ischemia compared with the control group. SB203580 treatment (1 micromol/L) only during IP blunted the infarct size limitation by IP (37.3+/-6.3% versus 7.4+/-2.1% in the IP group, P:<0.01) and attenuated either phosphorylation or translocation of HSP27 during IP. Although the SB203580 treatment throughout the preischemic and postischemic periods had no significant effect on infarct size (33.3+/-9.4%) in this model, treatment with SB203580 only during ischemia partially mimicked the infarct size limitation by IP (26.8+/-3.5%). Thus, transient p38 MAPK activation during ischemic preconditioning mainly mediates the cardioprotection followed by HSP27 phosphorylation and translocation in vivo in the canine heart.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sanada
authors.forename: M
authors.initials: M
authors.lastname: Kitakaze
authors.forename: P J
authors.initials: PJ
authors.lastname: Papst
authors.forename: K
authors.initials: K
authors.lastname: Hatanaka
authors.forename: H
authors.initials: H
authors.lastname: Asanuma
authors.forename: T
authors.initials: T
authors.lastname: Aki
authors.forename: Y
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: H
authors.initials: H
authors.lastname: Ogita
authors.forename: K
authors.initials: K
authors.lastname: Node
authors.forename: S
authors.initials: S
authors.lastname: Takashima
authors.forename: M
authors.initials: M
authors.lastname: Asakura
authors.forename: J
authors.initials: J
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Fukushima
authors.forename: A
authors.initials: A
authors.lastname: Ogai
authors.forename: T
authors.initials: T
authors.lastname: Kuzuya
authors.forename: H
authors.initials: H
authors.lastname: Mori
authors.forename: N
authors.initials: N
authors.lastname: Terada
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: M
authors.initials: M
authors.lastname: Hori
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003326:Coronary Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage; D007262:Infusions, Intravenous; D019157:Ischemic Preconditioning, Myocardial; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage; D015996:Survival Rate; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D007093:Imidazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580