β 1 -Blockade Prevents Post-Ischemic Myocardial Decompensation Via β 3 AR-Dependent Protective Sphingosine-1 Phosphate Signaling

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 demonstrated 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.

β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P2 modulation

“…Evidence for β3-AR/S1P cross-talk have been recently reported and this molecular interplay seems to be involved in physiopathological effects in different cellular contexts [30,46]. The occurrence of functional interplay between β3-AR and SK/S1P axis has been demonstrated by both pharmacological and RNA interference approach, and these results were further confirmed by the employment of a specific β3-AR agonist.…”

“…Literature data showed that S1P signaling strongly affects NB progression [27,29]. Notably, a recent paper reported a cross talk between the β3-AR and the S1P signaling in heart failure [30]. In view of this experimental data, we wondered whether these two pathways were potentially related in NB tumor biology.…”

U-shaped association between plasma sphingosine-1-phosphate levels and mortality in patients with chronic systolic heart failure: A prospective cohort study.

“…The S1PQ1 group had higher LVEDV than S1PQ2 group (230.46 (SD 83.55) vs 187.76 (SD 65.60), P=0.007). And Cannavo A et al [5] showed a mutual regulation mechanism between S1P/S1PR function and βadrenergic receptor function. These results suggest that an abnormal decline of plasma S1P may be associated with heavier ventricular remodelling.…”

“…In the model of post-ischemic HF, Cannavo A et al demonstrated that either cardiac or circulating levels of S1P are reduced compared to nonischemic control [6]. S1PR1 receptor expression decreased after myocardial infarction, and chronic S1P treatment could arrest post-MI HF progression [5]. Meanwhile, S1P lyase activation in the myocardium following ischemia leads to reduced S1P levels and that knockout mice for this enzyme exhibit higher S1P levels and smaller infarct size [18].…”

“…S1P is an intracellular secondary messenger, and it can also enter the circulation and bind to the G proteincoupled receptor family of sphingosine-1-phosphate receptors 1-5 to play an immunomodulatory role [3,4]. In recent years, studies have shown that S1P interacts with β-adrenergic receptors to play a role in simultaneously regulating immune system and sympathetic nervous system functions [5,6].…”