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Brief reoxygenation episodes during chronic hypoxia enhance posthypoxic recovery of LV function

Role of mitogen-activated protein kinase signaling pathways

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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.

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Acknowledgments

The study was supported by the Teo Rossi di Montelera Foundation, the Swiss Cardiology Foundation, the Fondation Vaudoise de Cardiologie, the Fondation Lausannoise de Transplantation, and the “Heart Remodeling in Health and Disease” program sponsored by the Swiss University Conference.

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Authors and Affiliations

  1. Department of Cardiology, University of Lausanne, CHUV, BH10 1011, Lausanne, Switzerland

    Sandrine Morel, Kathi Mujynya Ludunge, Sylvain Fleury, Lukas Kappenberger & Giuseppe Vassalli

  2. Department of Cardiovascular Surgery, University of Lausanne, Lausanne, Switzerland

    Sandrine Morel, Giuseppina Milano & Ludwig K. von Segesser

  3. Department of Cardiac Surgery, Alder Hey Royal Children Hospital, Liverpool, UK

    Antonio F. Corno

  4. Department of Medicine, San Paolo Hospital, Milan, Italy

    Michele Samaja

  5. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland

    Christophe Bonny

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  1. Sandrine Morel
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  2. Giuseppina Milano
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  3. Kathi Mujynya Ludunge
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  4. Antonio F. Corno
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  5. Michele Samaja
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  6. Sylvain Fleury
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  7. Christophe Bonny
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  8. Lukas Kappenberger
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  9. Ludwig K. von Segesser
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  10. Giuseppe Vassalli
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Correspondence to Giuseppe Vassalli.

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Returned for 1st revision: 25 November 2005 1st Revision received: 10 February 2006 Returned for 2nd revision: 28 November 2005 2nd Revision received: 3 March February 2006

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Morel, S., Milano, G., Ludunge, K.M. et al. Brief reoxygenation episodes during chronic hypoxia enhance posthypoxic recovery of LV function. Basic Res Cardiol 101, 336–345 (2006). https://doi.org/10.1007/s00395-006-0596-1

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  • DOI: https://doi.org/10.1007/s00395-006-0596-1

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