title: Sphingosine-1-Phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Postinfarction Left Ventricular Remodeling in a Porcine Model of Ischemia/Reperfusion.
abstract: BACKGROUND
  Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for the treatment of multiple sclerosis and exerts antiapoptotic properties. We hypothesized that sphingosine-1-phosphate receptor activation with fingolimod during acute myocardial infarction (MI) inhibits apoptosis, leading to increased myocardial salvage, reduced infarct size, and mitigated left ventricular (LV) remodeling in a porcine model of ischemia/reperfusion.
  
  
  RESULTS
  Ischemia/reperfusion was induced in pigs by balloon occlusion of the left anterior descending artery, followed by reperfusion. Animals randomly received fingolimod or saline (control). In short-term experiments, fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways in the infarct border zone 24 hours after MI, leading to decreased cardiomyocyte apoptosis and reduced myocardial oxidative stress. These effects were abolished by specific inhibitors of both pathways, demonstrating that fingolimod-induced cardioprotection was mediated by reperfusion injury salvage kinase and survivor activating factor enhancement pathways. In long-term experiments, fingolimod significantly improved myocardial salvage, reduced infarct size, and improved systolic LV function measured by cardiac magnetic resonance 1 week and 1 month after MI. Importantly, fingolimod mitigated the development of adverse post-MI LV remodeling 1 month after MI. Specifically, fingolimod treatment led to a significant reduction in LV mass, LV dilatation, and neurohormonal activation, and it preserved LV geometry. Furthermore, fingolimod decreased interstitial fibrosis, cardiomyocyte hypertrophy, and chronic activation of Akt and extracellular receptor kinase 1/2 in the remote noninfarcted myocardium.
  
  
  CONCLUSIONS
  Sphingosine-1-phosphate receptor activation with fingolimod during acute MI reduced infarct size via the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, improved systolic LV function, and mitigated post-MI LV remodeling. Our data strongly support a cardioprotective role for sphingosine-1-phosphate receptor activation during MI.
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.). carlos.santos-gallego@mssm.edu carlosgsantos@yahoo.es.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Santos-Gallego
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Torsten P
authors.initials: TP
authors.lastname: Vahl
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Georg
authors.initials: G
authors.lastname: Goliasch
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Belen
authors.initials: B
authors.lastname: Picatoste
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Teresa
authors.initials: T
authors.lastname: Arias
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Ida U
authors.initials: IU
authors.lastname: Njerve
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Javier
authors.initials: J
authors.lastname: Sanz
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Partho P
authors.initials: PP
authors.lastname: Sengupta
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.affiliation: From Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, Zena and Michael A. Wiener Cardiovascular Institute, and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, New York, NY (C.G.S.-G., T.P.V., G.G., B.P., T.A., K.I., I.U.N., J.S., J.N., P.P.S., R.J.H., V.F., J.J.B.); Columbia University Medical Center, New York Presbyterian Hospital, NY (T.P.V.); Department of Cardiology, Medical University of Vienna, Austria (G.G.); Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Norway (I.U.N.); and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (T.A., V.F.).
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D016879:Salvage Therapy / Q000379:methods*; D013552:Swine; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride
keywords: apoptosis; cardiovascular diseases; ischemia; models, animal; myocardial infarction; reperfusion injury; ventricular remodeling