TY - JOUR
T1 - β 1 -Blockade Prevents Post-Ischemic Myocardial Decompensation Via β 3 AR-Dependent Protective Sphingosine-1 Phosphate Signaling
AU - Cannavo, Alessandro
AU - Rengo, Giuseppe
AU - Liccardo, Daniela
AU - Pun, Andres
AU - Gao, Ehre
AU - George, Alvin J.
AU - Gambino, Giuseppina
AU - Rapacciuolo, Antonio
AU - Leosco, Dario
AU - Ibanez, Borja
AU - Ferrara, Nicola
AU - Paolocci, Nazareno
AU - Koch, Walter J.
N1 - Publisher Copyright:
© 2017 American College of Cardiology Foundation
PY - 2017/7/11
Y1 - 2017/7/11
N2 - Background Although β-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 β 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 β 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 β 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 β 1 AR-blockers display elevated circulating S1P levels, confirming that Meto promotes S1P secretion/signaling. Mechanistically, we found that Meto-induced S1P secretion is β 3 AR-dependent because Meto infusion in β 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 β 1 -blockers prevent HF progression in patients with ischemia, suggesting that β 3 AR dysfunction may account for limited/null efficacy in β 1 AR-blocker–insensitive HF subjects.
AB - Background Although β-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 β 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 β 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 β 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 β 1 AR-blockers display elevated circulating S1P levels, confirming that Meto promotes S1P secretion/signaling. Mechanistically, we found that Meto-induced S1P secretion is β 3 AR-dependent because Meto infusion in β 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 β 1 -blockers prevent HF progression in patients with ischemia, suggesting that β 3 AR dysfunction may account for limited/null efficacy in β 1 AR-blocker–insensitive HF subjects.
KW - myocardial infarction
KW - sphingosine 1-phosphate
KW - β-adrenergic receptors
KW - β-blocker
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U2 - 10.1016/j.jacc.2017.05.020
DO - 10.1016/j.jacc.2017.05.020
M3 - Article
C2 - 28683966
AN - SCOPUS:85021012529
SN - 0735-1097
VL - 70
SP - 182
EP - 192
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 2
ER -