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Molecular and Cellular Biochemistry

, Volume 373, Issue 1–2, pp 115–123 | Cite as

Uncoupled eNOS annihilates neuregulin-1β-induced cardioprotection: a novel mechanism in pharmacological postconditioning in myocardial infarction

  • Bernd EbnerEmail author
  • Stefan A. Lange
  • Thomas Eckert
  • Clementine Wischniowski
  • Annette Ebner
  • Rüdiger C. Braun-Dullaeus
  • Christof Weinbrenner
  • Carsten Wunderlich
  • Gregor Simonis
  • Ruth H. Strasser
Article

Abstract

Myocardial infarct size can be limited by pharmacological postconditioning (pPC) with cardioprotective agents. Cardioprotective effects of neuregulin-1β (NRG) via activation of protein kinase B (Akt) and downstream pathways like endothelial nitric oxide synthase (eNOS) have been postulated based on results from cell culture experiments. The purpose of this study was to investigate if eNOS may be involved in pPC with NRG. NRG application in an ex vivo mouse model (C57Bl6) of ischemia–reperfusion injury was analyzed. Unexpectedly, the infarct size increased when NRG was infused starting 5 min prior to reperfusion, even though protective Akt and GSK3β phosphorylation were enhanced. In eNOS deficient mice, however, NRG significantly reduced the infarct size. Co-infusion of NRG and l-arginine (Arg) lead to a reduction in infarct size in wild type animals. Electron paramagnetic resonance measurements revealed that NRG treatment prior to reperfusion leads to an enhanced release of reactive oxygen species compared to controls and this effect is blunted by co-infusion of Arg. This study documents the cardioprotective mechanisms of NRG signaling to be mediated by GSK3β inactivation. This is the first study to show that this protection fails in situations with dysfunctional eNOS. In eNOS deficient mice NRG exerts its protective effect via the GSK3β pathway, suggesting that the eNOS can limit cardioprotection. As dysfunctional eNOS has been described in cardiovascular risk factors like diabetes, hypertension, and hypercholesterolemia these findings can help to explain lack of postconditioning performance in models of cardiovascular co-morbidities.

Keywords

Myocardial infarction co-morbidities Dysfunctional endothelial nitric oxide synthase Postconditioning 

Abbreviations

Akt

Protein kinase B

Arg

l-Arginine

Cyt C

Cytochrome C

eNOS

Endothelial NO-synthase

ErbB-receptor

Erythroblastosis virus B oncogene

EPR

Electron paramagnetic resonance

GSK3β

Glycogen synthase kinase 3β

iPC

Ischemic postconditioning

LAD

Left anterior descending artery

LVDP

Left ventricular developed pressure

mPTP

Mitochondrial permeability transition pore

NRG

Neuregulin-1β

pPC

Pharmacological postconditioning

RISK

Reperfusion injury salvage kinase

ROS

Reactive oxygen species

Notes

Acknowledgments

We thank Janet Lehmann and Anita Männel for excellent technical assistance. The study was supported by the research prize of the Dresdener Herz-Kreislauf Tage awarded to Bernd Ebner.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Bernd Ebner
    • 1
    • 6
    Email author
  • Stefan A. Lange
    • 1
    • 3
  • Thomas Eckert
    • 1
  • Clementine Wischniowski
    • 1
  • Annette Ebner
    • 2
  • Rüdiger C. Braun-Dullaeus
    • 1
    • 4
  • Christof Weinbrenner
    • 1
    • 5
  • Carsten Wunderlich
    • 1
  • Gregor Simonis
    • 1
  • Ruth H. Strasser
    • 1
  1. 1.Department of Medicine/CardiologyHeart Center Dresden, University Hospital, University of Technology DresdenDresdenGermany
  2. 2.Laboratory of Experimental and Molecular CardiologyUniversity of Technology DresdenDresdenGermany
  3. 3.Klinikum WormsWormsGermany
  4. 4.Department of Cardiology, Angiology and PneumologyOtto-von-Guericke-Universität MagdeburgMagdeburgGermany
  5. 5.Medizinische Klinik I, Klinikum HanauHanauGermany
  6. 6.Herzzentrum DresdenDresdenGermany

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