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(Circulation. 2006;114:1403-1409.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P₃ Lysophospholipid Receptor

Gregor Theilmeier, MD^*; Christoph Schmidt, MD^*; Jörg Herrmann, MD; Petra Keul, BS; Michael Schäfers, MD; Ilka Herrgott, MD; Jan Mersmann, MD; Jan Larmann, MD; Sven Hermann, MD; Jörg Stypmann, MD; Otmar Schober, MD, PhD; Reinhard Hildebrand, MD; Rainer Schulz, MD; Gerd Heusch, MD; Michael Haude, MD; Karin von Wnuck Lipinski, PhD; Christine Herzog, PhD; Martina Schmitz, PhD; Raimund Erbel, MD; Jerold Chun, MD, PhD; Bodo Levkau, MD

From the Institute for Anatomy (G.T., I.H., J.M., J.L., R.H., C.H., M. Schmitz), Department of Anesthesiology and Intensive Care (G.T., C.S., I.H., J.M., J.L., C.H.), Department of Nuclear Medicine (M. Schäfers, S.H., O.S.), and Department of Cardiology and Angiology (J.S.), IZKF Münster, University Hospital, Münster, Germany; Department of Internal Medicine (J.H.), Mayo Clinic, Rochester, Minn; Institute of Pathophysiology, Center of Internal Medicine (P.K., R.S., G.H., K.v.W.L., B.L.) and Department of Cardiology (M.H., R.E.), West German Heart Center, University Hospital, Essen, Germany; and Department of Molecular Biology (J.C.), Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, Calif.

Correspondence to Bodo Levkau, MD, Institute of Pathophysiology, Center of Internal Medicine, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany (e-mail levkau{at}uni-essen.de), or Gregor Theilmeier, MD, Institute for Anatomy, Department of Anesthesiology and Intensive Care, University Hospital Münster, Vesaliusweg 2-4, 48149 Münster, Germany (e-mail theilmeier@anit.uni-muenster.de).

Received December 9, 2005; revision received July 25, 2006; accepted July 27, 2006.

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.

Methods and 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 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.

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