Figure 6
Role of S1P1 and S1P2 on observed LPS/PepG- and FTY720-mediated effects on cardiac function in mice.
(a) S1P receptors S1P1-3 and the activation of ERK and PI3K/Akt/eNOS through Gi coupled signaling pathways. S1P activates S1P receptors. The S1P mimetic FTY720 acts in its phosphorylated isoform as an unselective agonist on S1P1 and S1P3 and a selective functional antagonist on S1P1. S1P1 exclusively couples to Gi, while S1P2 and S1P3 couple to Gi, G12/13 and Gq. Coupling of S1P receptors to Gi leads to activation of the Ras/ERK pathway and the PI3K/Akt/eNOS pathway. SEW2871: S1P1 agonist. JTE 013: S1P2 antagonist. LY294002: PI3K inhibitor. S1P: sphingosine-1-phosphate. FTY720-P: phosphorylated FTY720. (b) Percentage ejection fraction was assessed via echocardiography 18 h subsequent to LPS/PepG co-administration in 2-month-old male C57BL/6J mice. At 1 h after LPS/PepG challenge mice were treated either with vehicle (10% DMSO) (n = 14), FTY720 (0.1 mg/kg) (n = 15) or the selective S1P1 agonist SEW2871 (1 mg/kg i.v.) (n = 3). Or mice received (45 min after LPS/PepG and 15 min prior to FTY720) the selective PI3K inhibitor LY294002 (0.3 mg/kg i.v.) (n = 6) or the selective S1P2 antagonist JTE 013 (1 mg/kg i.v.) (n = 6). One animal, which received JTE 013, died and was not included in the statistics. Data are expressed as means ± SEM for n number of observations. *P < 0.05 LPS/PepG + FTY720 vs. LPS/PepG + vehicle; #P < 0.05 vs. LPS/PepG + FTY720 (Kruskall-Wallis test with Dunn´s multiple comparisons test). (c) Summary of the experimental setup for acquisition of data provided in panel b.
