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Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion

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Abstract

Aging compromises restoration of the cardiac mechanical function during reperfusion. We hypothesized that this was due to an ampler release of mitochondrial reactive oxygen species (ROS). This study aimed at characterising ex vivo the mitochondrial ROS release during reperfusion in isolated perfused hearts of middle-aged rats. Causes and consequences on myocardial function of the observed changes were then evaluated. The hearts of rats aged 10- or 52-week old were subjected to global ischemia followed by reperfusion. Mechanical function was monitored throughout the entire procedure. Activities of the respiratory chain complexes and the ratio of aconitase to fumarase activities were determined before ischemia and at the end of reperfusion. H2O2 release was also evaluated in isolated mitochondria. During ischemia, middle-aged hearts displayed a delayed contracture, suggesting a maintained ATP production but also an increased metabolic proton production. Restoration of the mechanical function during reperfusion was however reduced in the middle-aged hearts, due to lower recovery of the coronary flow associated with higher mitochondrial oxidative stress indicated by the aconitase to fumarase ratio in the cardiac tissues. Surprisingly, activity of the respiratory chain complex II was better maintained in the hearts of middle-aged animals, probably because of an enhanced preservation of its membrane lipid environment. This can explain the higher mitochondrial oxidative stress observed in these conditions, since cardiac mitochondria produce much more H2O2 when they oxidize FADH2-linked substrates than when they use NADH-linked substrates. In conclusion, the lower restoration of the cardiac mechanical activity during reperfusion in the middle-aged hearts was due to an impaired recovery of the coronary flow and an insufficient oxygen supply. The deterioration of the coronary perfusion was explained by an increased mitochondrial ROS release related to the preservation of complex II activity during reperfusion.

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Acknowledgments

This work was supported by the National Institute of Agronomical Research (INRA, France) and the Université Joseph Fourier.

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Authors and Affiliations

  1. Laboratoire de Bioénergétique Fondamentale et Appliquée, INSERM U884, Université Joseph Fourier, BP 53, Grenoble Cedex 09, 38041, France

    Evangelia Mourmoura, Marie Leguen, Hervé Dubouchaud, Karine Couturier, Damien Vitiello, Xavier Leverve & Luc Demaison

  2. Université Joseph Fourier, Laboratoire de Bioénergétique Fondamentale et Appliquée, Grenoble Cedex 09, 38041, France

    Evangelia Mourmoura, Marie Leguen, Hervé Dubouchaud, Karine Couturier, Damien Vitiello, Xavier Leverve & Luc Demaison

  3. Département de Biologie Intégrée, CHU de Grenoble, Grenoble Cedex 09, 38043, France

    Jean-Luc Lafond

  4. Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA

    Melanie Richardson

  5. INRA, Unité CSGA, Dijon Cedex, 21065, France

    Luc Demaison

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  1. Evangelia Mourmoura
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  2. Marie Leguen
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  9. Luc Demaison
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Mourmoura, E., Leguen, M., Dubouchaud, H. et al. Middle age aggravates myocardial ischemia through surprising upholding of complex II activity, oxidative stress, and reduced coronary perfusion. AGE 33, 321–336 (2011). https://doi.org/10.1007/s11357-010-9186-0

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