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Selenium Pretreatment for Mitigation of Ischemia/Reperfusion Injury in Cardiovascular Surgery: Influence on Acute Organ Damage and Inflammatory Response

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ABSTRACT

Ischemia/reperfusion injury (IRI) contributes to morbidity and mortality after cardiovascular surgery requiring cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). Multi-organ damage is associated with substantial decreases of blood selenium (Se) levels in patients undergoing cardiac surgery with CPB. We compared the influence of a dietary surplus of Se and pretreatment with ebselen, a mimic of the selenoenzyme glutathione peroxidase, on IRI-induced tissue damage and inflammation. Male Wistar rats were fed either a Se-adequate diet containing 0.3 ppm Se or supplemented with 1 ppm Se (as sodium selenite) for 5 weeks. Two other groups of Se-adequate rats received intraperitoneal injection of ebselen (30 mg/kg) or DMSO (solvent control) before surgery. The animals were connected to a heart-lung-machine and underwent 45 min of global ischemia during circulatory arrest at 16 °C, followed by re-warming and reperfusion. Selenite and ebselen suppressed IRI-induced leukocytosis and the increase in plasma levels of tissue damage markers (AST, ALT, LDH, troponin) during surgery but did not prevent the induction of proinflammatory cytokines (IL-6, TNF-α). Both Se compounds affected phosphorylation and expression of proteins related to stress response and inflammation: Ebselen increased phosphorylation of STAT3 transcription factor in the heart and decreased phosphorylation of ERK1/2 MAP kinases in the lungs. Selenite decreased ERK1/2 phosphorylation and HSP-70 expression in the heart. Pretreatment with selenite or ebselen protected against acute IRI-induced tissue damage during CPB and DHCA. Potential implications of their different actions with regard to molecular stress markers on the recovery after surgery represent promising targets for further investigation.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

CPB:

Cardiopulmonary bypass

DHCA:

Deep hypothermic circulatory arrest

EFSA:

European food safety authority

ERK1/2:

Extracellular-regulated kinases-1/2

GPx:

Glutathione peroxidase

HO-1:

Heme oxygenase-1

HSP-70:

Heat shock protein-70

IL:

Interleukin

IRI:

Ischemia/reperfusion injury

LDH:

Lactate dehydrogenase

LPS:

Lipopolysaccharide

NAC:

N-acetyl cysteine

ROS/RNS:

Reactive oxygen and nitrogen species

SIRS:

Systemic inflammatory response syndrome

STAT3:

Signal transducer and activator of transcription-3

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

We thank A. Borchardt and T. Becher (Institute for Biochemistry and Molecular Biology I) for the excellent technical assistance. The authors are grateful for the continuous support of Dr. M. Sager and Dr. E. Engelhardt (Central animal care facility).

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    Authors and Affiliations

    1. Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University, Düsseldorf, Germany

      Holger Steinbrenner, Melanie Engels & Lena Wollschläger

    2. Department of Cardiovascular Surgery, University Hospital, Düsseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany

      Esra Bilgic, Antonio Pinto, Melanie Engels, Lena Wollschläger, Laura Döhrn, Udo Boeken, Payam Akhyari & Artur Lichtenberg

    3. Clinic for Anaesthesiology, Klinikum rechts der Isar, Technische Universität, Munich, Germany

      Kristine Kellermann

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    1. Holger Steinbrenner
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    Correspondence to Udo Boeken.

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    Funding

    This study was supported by a grant (F/07/12) of Deutsche Stiftung für Herzforschung (Frankfurt a.M., Germany) to Dr. Bilgic, Dr. Boeken, and Dr. Steinbrenner and by a grant (STE 1782/2-2) of Deutsche Forschungsgemeinschaft (DFG; Bonn, Germany) to Dr. Steinbrenner and by the generous support of the S. Bunnenberg Foundation.

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    The authors declare that they have no conflict of interest.

    Ethical Approval

    All applicable international, national, and institutional guidelines for the care and use of animals were followed.

    The study (approval number 87-51.04.2010.A334) was approved by the local authority LANUV (Landesamt für Natur, Umwelt und Verbraucherschutz NRW) and carried out in accordance with German and European guidelines of laboratory animal care.

    Additional information

    Drs. Akhyari and Lichtenberg are co-senior authors of this work.

    Holger Steinbrenner and Esra Bilgic contributed equally to this work.

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    Steinbrenner, H., Bilgic, E., Pinto, A. et al. Selenium Pretreatment for Mitigation of Ischemia/Reperfusion Injury in Cardiovascular Surgery: Influence on Acute Organ Damage and Inflammatory Response. Inflammation 39, 1363–1376 (2016). https://doi.org/10.1007/s10753-016-0368-5

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