title: High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor.
abstract: BACKGROUND
  All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport-independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury.
  
  
  RESULTS
  In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by approximately 20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL- and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P3 lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P3-deficient mice.
  
  
  CONCLUSIONS
  Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/reperfusion injury in vivo via an S1P3-mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia.
authors.affiliation: Institute for Anatomy, Department of Anesthesiology and Intensive Care, University Hospital Münster, Vesaliusweg 2-4, 48149 Münster, Germany. theilmeier@anit.uni-muenster.de
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmidt
authors.forename: Jörg
authors.initials: J
authors.lastname: Herrmann
authors.forename: Petra
authors.initials: P
authors.lastname: Keul
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Ilka
authors.initials: I
authors.lastname: Herrgott
authors.forename: Jan
authors.initials: J
authors.lastname: Mersmann
authors.forename: Jan
authors.initials: J
authors.lastname: Larmann
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hildebrand
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.forename: Michael
authors.initials: M
authors.lastname: Haude
authors.forename: Karin
authors.initials: K
authors.lastname: von Wnuck Lipinski
authors.forename: Christine
authors.initials: C
authors.lastname: Herzog
authors.forename: Martina
authors.initials: M
authors.lastname: Schmitz
authors.forename: Raimund
authors.initials: R
authors.lastname: Erbel
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha; C060506:sphingosine 1-phosphate; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D013110:Sphingosine; D019331:NG-Nitroarginine Methyl Ester