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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy

    M. R. Reforgiato, R. Paroni, M. Samaja, R. Ghidoni, A. Caretti & Paola Signorelli

  2. University Hospital Centre Vaudois (CHUV), Cardiovascular Research Center, Lausanne, Switzerland

    G. Milano

  3. Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy

    G. Milano

  4. Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, Catalan Institute of Advanced Chemistry (IQAC/CSIC), Barcelona, Spain

    G. Fabriàs & J. Casas

  5. Nanovector Srl., Turin, Italy

    P. Gasco

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  1. M. R. Reforgiato
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  10. Paola Signorelli
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Correspondence to Paola Signorelli.

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Reforgiato, M.R., Milano, G., Fabriàs, G. et al. Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury. Basic Res Cardiol 111, 12 (2016). https://doi.org/10.1007/s00395-016-0533-x

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