β1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via β3AR-Dependent Protective Sphingosine-1 Phosphate
Alessandro Cannavo1, Giuseppe Rengo2, Daniela Liccardo1
1Center for Translational Medicine and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Insights
Metoprolol, a beta-blocker, improves heart failure outcomes by restoring sphingosine-1-phosphate (S1P) signaling, a process dependent on beta-3 adrenergic receptors (β3AR). This uncovers a new mechanism for treating heart failure and explains why some patients don't respond to beta-blockers.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Beta-blockers improve survival in heart failure (HF), but mechanisms are unclear, and not all patients respond.
- A reciprocal down-regulation between β1-adrenergic receptors (ARs) and sphingosine-1-phosphate receptor-1 (S1PR1) was previously observed in cardiomyocytes.
Purpose of the Study:
- To investigate if metoprolol (Meto) improves post-myocardial infarction (MI) outcomes via restored S1PR1 signaling, beyond direct β1AR blockade.
- To elucidate the mechanisms underlying Meto's effects on cardiac structure and function.
Main Methods:
- In vitro studies using HEK293 cells and neonatal rat ventricular cardiomyocytes.
- In vivo studies in wild-type and β3AR knockout mice following MI.
Main Results:
- Metoprolol prevented catecholamine-induced S1PR1 down-regulation in vitro.
- Metoprolol arrested post-MI HF progression in mice, comparable to chronic S1P treatment.
- Human HF patients on β1AR blockers had elevated circulating S1P levels.
- Metoprolol-induced S1P secretion and HF improvement were β3AR-dependent in mice.
Conclusions:
- Uncovered a novel mechanism where β1-blockers prevent HF progression via S1PR1 signaling.
- β3AR dysfunction may explain the limited efficacy of β1AR-blockers in some HF patients.
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.
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