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Journal of Thrombosis and Thrombolysis

, Volume 46, Issue 1, pp 102–112 | Cite as

The effect of oxygen in Sirt3-mediated myocardial protection: a proof-of-concept study in cultured cardiomyoblasts

  • Philipp Diehl
  • Daniel S. Gaul
  • Jonas Sogl
  • Ulrike Flierl
  • Darren Henstridge
  • Juergen Pahla
  • Heiko Bugger
  • Maximilian Y. Emmert
  • Frank Ruschitzka
  • Christoph Bode
  • Thomas F. Lüscher
  • Martin Moser
  • Christian M. Matter
  • Karlheinz Peter
  • Stephan Winnik
Article
  • 127 Downloads

Abstract

Sirtuin 3 is a nicotinamide adenine dinucleotide dependent mitochondrial deacetylase that governs mitochondrial metabolism and oxidative defense. The demise in myocardial function following myocardial ischemia has been associated with mitochondrial dysfunction. Sirt3 maintains myocardial contractile function and protects from cardiac hypertrophy. The role of Sirt3 in ischemia is controversial. Our objective was to understand, under what circumstances Sirt3 is protective in different facets of ischemia, using an in vitro proof-of-concept approach based on simulated ischemia in cultured cardiomyoblasts. Cultured H9c2 cardiomyoblasts were subjected to hypoxia and/or serum deprivation, the combination of which we refer to as simulated ischemia. Apoptosis, as assessed by Annexin V staining in life-cell imaging and propidium-iodide inclusion in flow cytometry, was enhanced following simulated ischemia. Interestingly, serum deprivation was a stronger trigger of apoptosis than hypoxia. Knockdown of Sirt3 further increased apoptosis upon serum deprivation, whereas no such effect occurred upon additional hypoxia. Similarly, only upon serum deprivation but not upon simulated ischemia, silencing of Sirt3 led to a deterioration of mitochondrial function in extracellular flux analysis. In the absence of oxygen these Sirt3-dependent effects were abolished. These data indicate, that Sirt3-mediated myocardial protection is oxygen-dependent. Thus, mitochondrial respiration takes center-stage in Sirt3-dependent prevention of stress-induced myocardial damage.

Keywords

Sirt3 Cardiomyoblasts Ischemia Oxygen Mitochondrial function 

Notes

Funding

This work was funded by the National Health and Medical Research Council (NHMRC), the Victorian Government’s Operational Infrastructure Support Program, the Swiss National Science Foundation (310030, 146923), Matching Funds at the University of Zurich and the Zurich Heart House, Zurich, Switzerland. PD was supported by the German Research Foundation. JS was supported by the German Society of Cardiology. KP is a Principal Research Fellow of the NHMRC.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11239_2018_1677_MOESM1_ESM.docx (282 kb)
Supplementary material 1 (DOCX 282 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Philipp Diehl
    • 1
    • 2
  • Daniel S. Gaul
    • 3
  • Jonas Sogl
    • 1
    • 2
  • Ulrike Flierl
    • 2
    • 4
  • Darren Henstridge
    • 2
  • Juergen Pahla
    • 5
  • Heiko Bugger
    • 1
  • Maximilian Y. Emmert
    • 6
  • Frank Ruschitzka
    • 3
  • Christoph Bode
    • 1
  • Thomas F. Lüscher
    • 3
    • 5
    • 7
  • Martin Moser
    • 1
  • Christian M. Matter
    • 3
    • 6
    • 7
  • Karlheinz Peter
    • 1
    • 2
  • Stephan Winnik
    • 3
    • 5
  1. 1.Department of Cardiology & Angiology I, Heart Center Freiburg University, Faculty of MedicineUniversity of FreiburgFreiburgGermany
  2. 2.Baker IDI Heart and Diabetes InstituteMelbourneAustralia
  3. 3.Department of Cardiology, University Heart Center ZurichUniversity Hospital ZurichZurichSwitzerland
  4. 4.Hannover Medical SchoolHanoverGermany
  5. 5.Center for Molecular CardiologyUniversity of ZurichZurichSwitzerland
  6. 6.Swiss Center for Regenerative MedicineUniversity of ZurichZurichSwitzerland
  7. 7.Zurich Center for Human Integrative Physiology (ZHIP)University of ZurichZurichSwitzerland

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