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


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.


Myocardium Infarct Reperfusion Postconditioning Ceramide Inflammation Oxidative stress 



Glyceraldehyde-3-phosphate dehydrogenase


Heme-oxygenase 1








Left anterior descending


Liquid chromatography–mass spectrometry


Nuclear factor-erythroid 2-related factor 2


Reactive nitrogen species


Reactive oxygen species




Solid lipid nanocarriers


Serine palmitoyltransferase


Serine palmitoyltransferase, long chain base subunit 1


Serine palmitoyltransferase, long chain base subunit 2


Tris-buffered saline


Tumor necrosis factor-α


Triphenyl tetrazolium chloride



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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