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Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury

  • M. R. Reforgiato
  • G. Milano
  • G. Fabriàs
  • J. Casas
  • P. Gasco
  • R. Paroni
  • M. Samaja
  • R. Ghidoni
  • A. Caretti
  • Paola SignorelliEmail author
Original Contribution

Abstract

The injury caused by myocardial reperfusion after ischemia can be contained by interventions aimed at reducing the inflammation and the oxidative stress that underlie exacerbation of tissue damage. Sphingolipids are a class of structural and signaling lipid molecules; among them, the inflammation mediator ceramide accumulates in the myocardium upon ischemia/reperfusion. Here, we show that, after transient coronary occlusion in mice, an increased de novo ceramide synthesis takes place at reperfusion in the ischemic area surrounding necrosis (area at risk). This correlates with the enhanced expression of the first and rate-limiting enzyme of the de novo pathway, serine palmitoyltransferase (SPT). The intraventricular administration at reperfusion of myriocin, an inhibitor of SPT, significantly protected the area at risk from damage, reducing the infarcted area by 40.9 % relative to controls not treated with the drug. In the area at risk, myriocin downregulated ceramide, reduced the content in other mediators of inflammation and reactive oxygen species, and activated the Nrf2–HO1 cytoprotective response. We conclude that an enhanced ceramide synthesis takes part in ischemia/reperfusion injury and that myriocin treatment can be proposed as a strategy for myocardial pharmacological postconditioning.

Keywords

Myocardium Infarct Reperfusion Postconditioning Ceramide Inflammation Oxidative stress 

Abbreviations

Gapdh

Glyceraldehyde-3-phosphate dehydrogenase

HO1

Heme-oxygenase 1

I/R

Ischemia/reperfusion

IL-1β

Interleukin-1β

IL-6

Interleukin-6

LAD

Left anterior descending

LCMS

Liquid chromatography–mass spectrometry

Nrf2

Nuclear factor-erythroid 2-related factor 2

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

S1P

Sphingosine-1-phosphate

SLN

Solid lipid nanocarriers

SPT

Serine palmitoyltransferase

SPTLC1

Serine palmitoyltransferase, long chain base subunit 1

SPTLC2

Serine palmitoyltransferase, long chain base subunit 2

TBS

Tris-buffered saline

TNF-α

Tumor necrosis factor-α

TTC

Triphenyl tetrazolium chloride

Notes

Acknowledgments

Financial support from the institutional grants of the University of Milan and PhD program in “Molecular and Translational Medicine” of the University of Milan, Italy, is acknowledged. We thank Dr. Paola Bianciardi for her precious experimental support. We specially thank Prof. Andrea Gallina, Health Sciences Department, University of Milan, for thorough revision of the manuscript and helpful discussion.

Supplementary material

395_2016_533_MOESM1_ESM.pdf (517 kb)
Supplementary material 1 (PDF 516 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • M. R. Reforgiato
    • 1
  • G. Milano
    • 2
    • 3
  • G. Fabriàs
    • 4
  • J. Casas
    • 4
  • P. Gasco
    • 5
  • R. Paroni
    • 1
  • M. Samaja
    • 1
  • R. Ghidoni
    • 1
  • A. Caretti
    • 1
  • Paola Signorelli
    • 1
    Email author
  1. 1.Department of Health SciencesUniversity of Milan, San Paolo HospitalMilanItaly
  2. 2.University Hospital Centre Vaudois (CHUV), Cardiovascular Research CenterLausanneSwitzerland
  3. 3.Vascular Biology and Regenerative Medicine UnitCentro Cardiologico Monzino-IRCCSMilanItaly
  4. 4.Research Unit on BioActive Molecules, Department of Biomedicinal ChemistryCatalan Institute of Advanced Chemistry (IQAC/CSIC)BarcelonaSpain
  5. 5.Nanovector Srl.TurinItaly

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