Metoprolol prevents post‐ischemic myocardial decompensation via β 3 AR‐dependent protective Sphingosine‐1 phosphate signaling

Background β‐blockers increase survival in heart failure (HF) patients; however, the mechanisms behind this protection are not fully understood. Further, a high percentage of HF patients cannot tolerate or are non‐responders to b‐blockade. It is known that sympathetic catecholamine overactivation of β 1 ‐adrenergic receptors (ARs) leads to sphingosine‐1‐phosphate (S1P) receptor‐1 (S1PR 1 ) down‐regulation, contributing to HF progression since S1P‐SIPR 1 signaling is cardioprotective. Hence, it is plausible that, in addition to direct β 1 AR blockade actions, β 1 AR blockers may improve decompensated heart function by restoring S1PR 1 signals. Here, we tested this novel hypothesis, and sought to determine the mechanisms underlying the positive impact of β 1 AR blockade and S1PR 1 in the ischemic heart after myocardial infarction (MI) and during HF progression. Methods In vitro we tested the effects of Metoprolol (Meto) in HEK293 cells and in ventricular cardiomyocytes isolated from neonatal rats (NRVMs). In vivo we assessed the effects and the potential mechanism of Meto in Wild‐type and β 3 AR knockout (KO) mice. Results Here we report that the β 1 AR‐blocker Meto prevents Isoproterenol‐ (βAR agonist) but not S1P‐induced S1PR 1 down‐regulation in vitro . In vivo, infarcted mice treated with Meto or S1P (1 week after MI for 3 weeks) displayed attenuated cardiac function and reversed adverse LV remodeling. Combining S1P and Meto did not further improve post‐MI outcome. Previous evidence shows that Meto increases cardiac β 3 AR levels and activity, and in adipocytes β 3 AR participates in S1P secretion. Hence, we next measured cardiac Sphingosine kinase 1 (SphK1), the enzyme responsible for S1P secretion, along with circulating S1P levels, in both WT and β 3 AR KO mice. Circulating S1P and cardiac SphK1 protein levels were significantly reduced in MI vs. sham‐operated mice, and this effect was almost completely prevented by Meto. Conversely, β 3 AR KO mice displayed markedly reduced S1P and SphK1 levels, both under control and MI condition, and Meto failed to restore their levels in these animals. Congruent with this, Meto‐treatment did not ameliorate post‐MI dysfunction in β 3 AR KO mice. Importantly, human HF patients on β1AR‐blockers have elevated circulating S1P levels suggesting Meto is linked to S1P secretion and signaling. Conclusions Our study uncovers a previously unrecognized mechanism by which β1‐blockers prevents disease progression in ischemic HF patients and this is dependent on b 3 ARs and S1P secretion. Importantly, it suggests that a mechanism of b‐blocker non‐responders may be due to β 3 AR‐dysfunction. Support or Funding Information American Heart Association‐GRA Winter 2016 Postdoctoral Fellowship‐16POST30980005