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

Abstract

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). 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. 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. 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. 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.