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

BACKGROUND Although beta-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 beta(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 beta(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 beta(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 beta(1)AR-blockers display elevated circulating S1P levels, confirming that Meto promotes S1P secretion/signaling. Mechanistically, we found that Meto-induced S1P secretion is beta(3)AR-dependent because Meto infusion in beta(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 beta(1)-blockers prevent HF progression in patients with ischemia, suggesting that b3AR dysfunction may account for limited/null efficacy in beta(1)AR-blocker-insensitive HF subjects. (C) 2017 by the American College of Cardiology Foundation.