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, Christoph Schmidt, Joerg Herrmann, Petra Keul, Michael Schäfers, Ilka Herrgott, Jan Mersmann, Jan Larmann, Sven Hermann, Jörg Stypmann, Otmar Schober, Reinhard Hildebrand, Rainer Schulz, Gerd Heusch, Michael Haude, Karin Von Wnuck Lipinski, Christine Herzog, Martina Schmitz, Raimund Erbel, Jerold ChunBodo Levkau

Research output: Contribution to journalArticle

269 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)1403-1409
Number of pages7
JournalCirculation
Volume114
Issue number13
DOIs
StatePublished - Sep 1 2006

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Lysophospholipid Receptors
Lysosphingolipid Receptors
HDL Lipoproteins
Reperfusion Injury
Cardiac Myocytes
Myocardial Ischemia
Nitric Oxide
Biological Transport
Apoptosis
Myocardial Reperfusion Injury
Myocardial Reperfusion
Sphingolipids
Neutrophil Infiltration
Nitric Oxide Synthase
Infarction
Endothelium
Leukocytes
Myocardial Infarction
Cholesterol
sphingosine 1-phosphate

Keywords

  • Apoptosis
  • Endothelium
  • Inflammation
  • Lipoproteins
  • Microcirculation
  • Reperfusion
  • Sphingolipids

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. / Theilmeier, Gregor; Schmidt, Christoph; Herrmann, Joerg; Keul, Petra; Schäfers, Michael; Herrgott, Ilka; Mersmann, Jan; Larmann, Jan; Hermann, Sven; Stypmann, Jörg; Schober, Otmar; Hildebrand, Reinhard; Schulz, Rainer; Heusch, Gerd; Haude, Michael; Lipinski, Karin Von Wnuck; Herzog, Christine; Schmitz, Martina; Erbel, Raimund; Chun, Jerold; Levkau, Bodo.

In: Circulation, Vol. 114, No. 13, 01.09.2006, p. 1403-1409.

Research output: Contribution to journalArticle

Theilmeier, G, Schmidt, C, Herrmann, J, Keul, P, Schäfers, M, Herrgott, I, Mersmann, J, Larmann, J, Hermann, S, Stypmann, J, Schober, O, Hildebrand, R, Schulz, R, Heusch, G, Haude, M, Lipinski, KVW, Herzog, C, Schmitz, M, Erbel, R, Chun, J & Levkau, B 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', Circulation, vol. 114, no. 13, pp. 1403-1409. https://doi.org/10.1161/CIRCULATIONAHA.105.607135
Theilmeier, Gregor ; Schmidt, Christoph ; Herrmann, Joerg ; Keul, Petra ; Schäfers, Michael ; Herrgott, Ilka ; Mersmann, Jan ; Larmann, Jan ; Hermann, Sven ; Stypmann, Jörg ; Schober, Otmar ; Hildebrand, Reinhard ; Schulz, Rainer ; Heusch, Gerd ; Haude, Michael ; Lipinski, Karin Von Wnuck ; Herzog, Christine ; Schmitz, Martina ; Erbel, Raimund ; Chun, Jerold ; Levkau, Bodo. / High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. In: Circulation. 2006 ; Vol. 114, No. 13. pp. 1403-1409.
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T1 - High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor

AU - Theilmeier, Gregor

AU - Schmidt, Christoph

AU - Herrmann, Joerg

AU - Keul, Petra

AU - Schäfers, Michael

AU - Herrgott, Ilka

AU - Mersmann, Jan

AU - Larmann, Jan

AU - Hermann, Sven

AU - Stypmann, Jörg

AU - Schober, Otmar

AU - Hildebrand, Reinhard

AU - Schulz, Rainer

AU - Heusch, Gerd

AU - Haude, Michael

AU - Lipinski, Karin Von Wnuck

AU - Herzog, Christine

AU - Schmitz, Martina

AU - Erbel, Raimund

AU - Chun, Jerold

AU - Levkau, Bodo

PY - 2006/9/1

Y1 - 2006/9/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Endothelium

KW - Inflammation

KW - Lipoproteins

KW - Microcirculation

KW - Reperfusion

KW - Sphingolipids

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