High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor.
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.
Theilmeier
Gregor
G
Institute for Anatomy, Department of Anesthesiology and Intensive Care, University Hospital Münster, Vesaliusweg 2-4, 48149 Münster, Germany. theilmeier@anit.uni-muenster.de
Schmidt
Christoph
C
Herrmann
Jörg
J
Keul
Petra
P
Schäfers
Michael
M
Herrgott
Ilka
I
Mersmann
Jan
J
Larmann
Jan
J
Hermann
Sven
S
Stypmann
Jörg
J
Schober
Otmar
O
Hildebrand
Reinhard
R
Schulz
Rainer
R
Heusch
Gerd
G
Haude
Michael
M
von Wnuck Lipinski
Karin
K
Herzog
Christine
C
Schmitz
Martina
M
Erbel
Raimund
R
Chun
Jerold
J
Levkau
Bodo
B
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
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