title: Brief reoxygenation episodes during chronic hypoxia enhance posthypoxic recovery of LV function: role of mitogen-activated protein kinase signaling pathways.
abstract: Children with congenital cyanotic heart defects have worse outcomes after surgical repair of their heart defects compared with noncyanotic ones. Institution of extracorporeal circulation in these children exposes the cyanotic heart to reoxygenation injury. Mitogen-activated protein kinase (MAPK) signaling cascades are major regulators of cardiomyocyte function in acute hypoxia and reoxygenation. However, their roles in chronic hypoxia are incompletely understood. We determined myocardial activation of the three major MAPKs, c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase-1/2 (ERK1/2), and p38-MAPK in adult rats exposed to hypoxia (FIO2=0.10) for varying periods of time. Myocardial function was analyzed in isolated perfused hearts. Acute hypoxia stimulated JNK and p38-MAPK activation. Chronic hypoxia (2 weeks) was associated with increased p38-MAPK (but not JNK) activation, increased apoptosis, and impaired posthypoxic recovery of LV function. Brief normoxic episodes (1 h/day) during chronic hypoxia abolished p38-MAPK activation, stimulated MEK-ERK1/2 activation modestly, and restored posthypoxic LV function. In vivo p38-MAPK inhibition by SB203580 or SB202190 in chronically hypoxic rats restored posthypoxic LV function. These results indicate that sustained hypoxemia maintains p38-MAPK in a chronically activated state that predisposes to myocardial impairment upon reoxygenation. Brief normoxic episodes during chronic hypoxia prevent p38-MAPK activation and restore posthypoxic recovery of myocardial function.
authors.affiliation: Department of Cardiology, University of Lausanne, CHUV, BH10 1011, Lausanne, Switzerland, and Department of Cardiac Surgery, Alder Hey Royal Children Hospital, Liverpool, UK.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Morel
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Milano
authors.forename: Kathi Mujynya
authors.initials: KM
authors.lastname: Ludunge
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Corno
authors.forename: Michele
authors.initials: M
authors.lastname: Samaja
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fleury
authors.forename: Christophe
authors.initials: C
authors.lastname: Bonny
authors.forename: Lukas
authors.initials: L
authors.lastname: Kappenberger
authors.forename: Ludwig K
authors.initials: LK
authors.lastname: von Segesser
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vassalli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology* / Q000628:therapy; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010100:Oxygen / Q000502:physiology* / Q000627:therapeutic use; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016277:Ventricular Function, Left; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen