title: Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury.
abstract: BACKGROUND
  New evidence shows that high density lipoproteins (HDL) have protective effects beyond their role in reverse cholesterol transport. Reconstituted HDL (rHDL) offer an attractive means of clinically exploiting these novel effects including cardioprotection against ischemia reperfusion injury (IRI). However, basic rHDL composition is limited to apolipoprotein AI (apoAI) and phospholipids; addition of bioactive compound may enhance its beneficial effects.
  
  
  OBJECTIVE
  The aim of this study was to investigate the role of rHDL in post-ischemic model, and to analyze the potential impact of sphingosine-1-phosphate (S1P) in rHDL formulations.
  
  
  RESULTS
  The impact of HDL on IRI was investigated using complementary in vivo, ex vivo and in vitro IRI models. Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p<0.01). Treatment with rHDL of basic formulation (apoAI + phospholipids) had a non-significant impact on cell death in vitro and on the infarct size ex vivo and in vivo. In contrast, rHDL containing S1P had a highly significant, protective influence ex vivo, and in vivo (-50%, p<0.01). This impact was comparable with the effects observed with native HDL. Pro-survival signaling proteins, Akt, STAT3 and ERK1/2 were similarly activated by HDL and rHDL containing S1P both in vitro (isolated cardiomyocytes) and in vivo.
  
  
  CONCLUSIONS
  HDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P. The protective impact of HDL appears to target directly the cardiomyocyte.
authors.affiliation: Service of Endocrinology, Diabetology, Hypertension and Nutrition, Department of Internal Medicine, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Brulhart-Meynet
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland; Service of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.affiliation: Service of Endocrinology, Diabetology, Hypertension and Nutrition, Department of Internal Medicine, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Jonas
authors.initials: J
authors.lastname: Brinck
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland; Service of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland; Department of human protein sciences, Geneva University Hospital, Geneva, Switzerland; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine. IRCCS Azienda Ospedaliera Universitaria San Martino-IST Instituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.affiliation: Unit of Toxicology, CURML, University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Prost
authors.affiliation: Unit of Toxicology, CURML, University of Lausanne, Lausanne, Switzerland.
authors.forename: Aurelien
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Katia
authors.initials: K
authors.lastname: Galan
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.affiliation: Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Science, University of Cape Town, Cape Town, South Africa.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pedretti
authors.affiliation: Service of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland; Department of human protein sciences, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.affiliation: Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Science, University of Cape Town, Cape Town, South Africa.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecour
authors.affiliation: Service of Endocrinology, Diabetology, Hypertension and Nutrition, Department of Internal Medicine, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Richard W
authors.initials: RW
authors.lastname: James
authors.affiliation: Service of Endocrinology, Diabetology, Hypertension and Nutrition, Department of Internal Medicine, Faculty of Medicine, Geneva, Switzerland.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Frias
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D008075:Lipoproteins, HDL / Q000494:pharmacology* / Q000627:therapeutic use; D008246:Lysophospholipids / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D050796:STAT3 Transcription Factor; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013110:Sphingosine