Carlos G Santos-Gallego1, Torsten P Vahl2, Georg Goliasch2, Belen Picatoste2, Teresa Arias2, Kiyotake Ishikawa2, Ida U Njerve2, Javier Sanz2, Jagat Narula2, Partho P Sengupta2, Roger J Hajjar2, Valentin Fuster2, Juan J Badimon2. 1. 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. 2. 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.).
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. METHODS AND 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.
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. METHODS AND 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: Bryan S Yung; Cameron S Brand; Sunny Y Xiang; Charles B B Gray; Christopher K Means; Hugh Rosen; Jerold Chun; Nicole H Purcell; Joan Heller Brown; Shigeki Miyamoto Journal: J Mol Cell Cardiol Date: 2016-12-23 Impact factor: 5.000
Authors: Steven L Swendeman; Yuquan Xiong; Anna Cantalupo; Hui Yuan; Nathalie Burg; Yu Hisano; Andreane Cartier; Catherine H Liu; Eric Engelbrecht; Victoria Blaho; Yi Zhang; Keisuke Yanagida; Sylvain Galvani; Hideru Obinata; Jane E Salmon; Teresa Sanchez; Annarita Di Lorenzo; Timothy Hla Journal: Sci Signal Date: 2017-08-15 Impact factor: 8.192
Authors: Christian Cadeddu; Alessandra Piras; Mariele Dessì; Clelia Madeddu; Giovanni Mantovani; Mario Scartozzi; Andreas Hagendorff; Paolo Colonna; Giuseppe Mercuro Journal: Int J Cardiovasc Imaging Date: 2016-10-01 Impact factor: 2.357