β1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via β3AR-Dependent Protective Sphingosine-1 Phosphate Signaling

Alessandro Cannavo, Giuseppe Rengo, Daniela Liccardo, Andres Pun, Ehre Gao, Alvin J George, Giuseppina Gambino, Antonio Rapacciuolo, Dario Leosco, Borja Ibanez, Nicola Ferrara, Nazareno Paolocci, Walter J Koch

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Abstract

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 β1-adrenergic receptors (ARs) and the cardioprotective sphingosine-1-phosphate (S1P) receptor-1 (S1PR1).

OBJECTIVES: The authors hypothesized that, in addition to salutary actions due to direct β1AR-blockade, agents such as metoprolol (Meto) may improve post-myocardial infarction (MI) structural and functional outcomes via restored S1PR1 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 β3AR knockout mice.

RESULTS: Here we report that, in vitro, Meto prevents catecholamine-induced down-regulation of S1PR1, 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 β1AR-blockers display elevated circulating S1P levels, confirming that Meto promotes S1P secretion/signaling. Mechanistically, we found that Meto-induced S1P secretion is β3AR-dependent because Meto infusion in β3AR 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 β1-blockers prevent HF progression in patients with ischemia, suggesting that β3AR dysfunction may account for limited/null efficacy in β1AR-blocker-insensitive HF subjects.

Original languageEnglish
Pages (from-to)182-192
Number of pages11
JournalJournal of the American College of Cardiology
Volume70
Issue number2
DOIs
Publication statusPublished - Jul 11 2017

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Keywords

  • Journal Article

Cite this

Cannavo, A., Rengo, G., Liccardo, D., Pun, A., Gao, E., George, A. J., Gambino, G., Rapacciuolo, A., Leosco, D., Ibanez, B., Ferrara, N., Paolocci, N., & Koch, W. J. (2017). β1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via β3AR-Dependent Protective Sphingosine-1 Phosphate Signaling. Journal of the American College of Cardiology, 70(2), 182-192. https://doi.org/10.1016/j.jacc.2017.05.020