The Role of Microdomains in Beta-Adrenoreceptor Signalling266Metoprolol induces cardiac beta-3 adrenergic receptor and Sphingosine 1 phosphate receptor 1 signals to prevent adverse Left-ventricle remodeling and dysfunction after myocardial infarction267PDE8 is a novel regulator of cAMP signaling in human atrial fibrillation268B-blocker therapy in heart failure reduces migratory and proliferative properties of primarily cultured failing cardiac fibroblasts via reduction of g protein-coupled receptor kinase-2 expression

Le résumé fourni par la source

Background: β-adrenergic receptor (AR)-blockers are fore-front therapies against myocardial infarction (MI)-induced and other forms of heart failure (HF). Mechanisms accounting for these beneficial effects remain however only partially understood. In particular, due to the difference in receptor targeting and to the great variability in human HF-patients response, the specific mechanism of action of β-blockers is still under investigation. We have recently demonstrated, in an animal model of HF, that a reciprocal down-regulation occurs between β1AR and the cardioprotective sphingosine-1-phosphate (S1P) receptor-1 (S1PR1). Purpose: Hence, we hypothesize that, in addition to salutary actions due to direct β1AR blockade, agents such as metoprolol improve post-MI structural and functional outcome via restored protective S1PR1 signal, and we sought to determine mechanisms accounting for this effect. Methods and Results: In HEK293 cells and in in vitro cardiomyocytes, metoprolol (Meto) prevented isoproterenol (βAR agonist)-dependent S1PR1 down-regulation. Treatment of infarcted mice with Meto or S1P (one week after MI for 3 weeks) markedly ameliorated cardiac function and prevented remodeling, while preserving cardiac plasma membrane S1PR1 whose levels were down-regulated in untreated MI mice. Next, we co-infused infarcted mice with S1P and Meto, and found no additional beneficial effects. Since previous evidence attests that Meto can increase cardiac β3ARs levels and activity, and this receptor in adypocytes is responsible for S1P secretion, we measured basal and Meto-stimulated cardiac Sphingosine kinase 1 (SphK1), the enzyme responsible for S1P secretion, and circulating S1P levels in β3AR KO mice. These animals displayed markedly reduced levels of both, not rescued by Meto. Importantly, the β1AR blocker did not ameliorate post-MI dysfunction in β3AR KO mice. Conclusions: β1-blockers enhance β3AR-signaling, promoting the secretion of S1P that, in turn, activates the S1PR1 signalling. These signalling interactions represent a previously unrecognized mechanism whereby βAR blockers prevent post-MI decompensation and adverse remodelling.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.