SEW2871 attenuates myocyte necroptosis in heart failure through inhibition of oxidative stress and inflammatory cytokines.

Background And Purpose: Sphingosine-1-phosphate (S1P)/S1P receptor signalling exerts cardioprotective effects. However, the effect of the selective S1P receptor agonist SEW2871 on myocyte necroptosis in heart failure and the underlying mechanisms are unknown. In the present study, we tested the hypothesis that SEW2871 attenuates myocyte necroptosis in heart failure through inhibition of oxidative stress and inflammatory cytokines.

Experimental Approach: Eight-week-old male C57BL/6J mice underwent myocardial infarction (MI) or sham operation. The animals were randomized to receive SEW2871 (5 mg·kg·day, i.p) or placebo for 4 weeks.

Key Results: MI mice exhibited the increases in left ventricular (LV) end-diastolic dimension, LV end-systolic dimension, LV mass and lung weight and a decrease in LV ejection fraction, indicating LV dilation, LV systolic dysfunction and lung congestion, and these alterations were attenuated by the SEW2871 treatment. Myocardial expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin-1β and interleukin-6, and phosphorylated RIPK1 (p-RIPK1), p-RIPK3 and p-MLKL, reflective of their respective kinase activities, markers of necroptosis, was markedly increased in the MI placebo group, and the increase was abolished by the SEW2871 treatment. Similarly, intracellular levels of reactive oxygen species, inflammatory cytokines, p-RIPK1, p-RIPK3 and p-MLKL protein expression were increased in H9C2 cardiomyocytes under mimic ischaemia and the increases were prevented by the SEW2871 treatment.

Conclusion And Implications: The selective S1P receptor agonist SEW2871 attenuates myocyte necroptosis through inhibition of oxidative stress and inflammatory cytokines, leading to improvement of LV remodelling and function in heart failure.