b 1 -Blockade Prevents Post-Ischemic Myocardial Decompensation Via b 3 AR-Dependent Protective Sphingosine-1 Phosphate Signaling Alessandro Cannavo, PHD, a Giuseppe Rengo, MD, PHD, b,c Daniela Liccardo, PHD, a Andres Pun, DVM, MSC, d Ehre Gao, MD, PHD, a Alvin J. George, BSC, a Giuseppina Gambino, PHD, b Antonio Rapacciuolo, MD, PHD, e Dario Leosco, MD, PHD, b Borja Ibanez, MD, PHD, d,f,g Nicola Ferrara, MD, PHD, b,c Nazareno Paolocci, MD, PHD, h,i Walter J. Koch, PHD a ABSTRACT BACKGROUND Although b-blockers increase survival in patients with heart failure (HF), the mechanisms behind this protection are not fully understood, and not all patients with HF respond favorably to them. We recently showed that, in cardiomyocytes, a reciprocal down-regulation occurs between b 1 -adrenergic receptors (ARs) and the cardioprotective sphingosine-1-phosphate (S1P) receptor- 1 (S1PR 1 ). OBJECTIVES The authors hypothesized that, in addition to salutary actions due to direct b 1 AR-blockade, agents such as metoprolol (Meto) may improve post–myocardial infarction (MI) structural and functional outcomes via restored S1PR 1 signaling, and sought to determine mechanisms accounting for this effect. METHODS We tested the in vitro effects of Meto in HEK293 cells and in ventricular cardiomyocytes isolated from neonatal rats. In vivo, we assessed the effects of Meto in MI wild-type and b 3 AR knockout mice. RESULTS Here we report that, in vitro, Meto prevents catecholamine-induced down-regulation of S1PR 1 , a major cardiac protective signaling pathway. In vivo, we show that Meto arrests post-MI HF progression in mice as much as chronic S1P treatment. Importantly, human HF subjects receiving b 1 AR-blockers display elevated circulating S1P levels, confirming that Meto promotes S1P secretion/signaling. Mechanistically, we found that Meto-induced S1P secretion is b 3 AR-dependent because Meto infusion in b 3 AR knockout mice does not elevate circulating S1P levels, nor does it ameliorate post-MI dysfunction, as in wild-type mice. CONCLUSIONS Our study uncovers a previously unrecognized mechanism by which b 1 -blockers prevent HF progression in patients with ischemia, suggesting that b 3 AR dysfunction may account for limited/null efficacy in b 1 AR-blocker–insensitive HF subjects. (J Am Coll Cardiol 2017;70:182–92) © 2017 by the American College of Cardiology Foundation. From the a Center for Translational Medicine and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; b Department of Translational Medical Science, University of Naples Federico II, Naples, Italy; c Istituti Clinici Scientifici Maugeri SpA Società Benefit, Telese Terme Institute, Telese Terme (BN), Italy; d Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; e Department of Advanced Medical Science, University of Naples Federico II, Naples, Italy; f IIS-Fundación Jiménez Díaz, Madid, Spain; g CIBER de enfermedades car- diovasculares, Madrid, Spain; h Division of Cardiology, Johns Hopkins University Medical Institutions, Baltimore, Maryland; and the i Department of Experimental Medicine, University of Perugia, Perugia, Italy. Dr. Koch hasreceived NIH grants R37 HL061690, RO1 HL088503, P01 HL08806, P01 HL075443, and P01 HK091799. Dr. Paolocci received NIH grant RO1 HL063030; and an AHA Grant- in-Aid 17070027. Dr. Cannavo has received a grant from the American Heart Association, 16POST30980005. Dr. Rengo has received a grant from the Italian Ministry of Health-GR-2011-02346878. The CNIC is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Cannavo and Rengo contributed equally to this work and are joint first authors. Joel S. Karliner, MD, served as Guest Editor for this paper. Manuscript received December 23, 2016; revised manuscript received May 8, 2017, accepted May 8, 2017. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 70, NO. 2, 2017 ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2017.05.020