Published Online
on September 18, 2006

A more recent version of this article appeared on September 26, 2006

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Submitted on December 9, 2005
Revised on July 25, 2006
Accepted on July 27, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: levkau{at}uni-essen.de.

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.

Key words: lipoproteins • inflammation • apoptosis • endothelium • sphingolipids • microcirculation • reperfusion

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