title: Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury.
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.
authors.affiliation: Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Reforgiato
authors.affiliation: University Hospital Centre Vaudois (CHUV), Cardiovascular Research Center, Lausanne, Switzerland.|Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Milano
authors.affiliation: Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, Catalan Institute of Advanced Chemistry (IQAC/CSIC), Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Fabriàs
authors.affiliation: Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, Catalan Institute of Advanced Chemistry (IQAC/CSIC), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Casas
authors.affiliation: Nanovector Srl., Turin, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Gasco
authors.affiliation: Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Paroni
authors.affiliation: Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Samaja
authors.affiliation: Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Ghidoni
authors.affiliation: Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Caretti
authors.affiliation: Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy. paola.signorelli@unimi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Signorelli
mesh_terms: D000818:Animals; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D057775:Ischemic Postconditioning / Q000379:methods*; D008297:Male; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; C001996:thermozymocidin
keywords: Ceramide; Infarct; Inflammation; Myocardium; Oxidative stress; Postconditioning; Reperfusion