Sinusoidal protection by sphingosine-1-phosphate receptor 1 agonist in liver ischemia-reperfusion injury

Abstract

Background: Functional and structural damages in sinusoidal endothelial cells (SECs) have a crucial role during hepatic ischemia-reperfusion injury (IRI). In regulating endothelial function, sphingosine-1-phosphate receptor 1 (S1PR1), which is a G protein-coupled receptor, has an important role. The present study aimed to clarify whether SEW2871, a selective S1PR1 agonist, can attenuate hepatic damage caused by hepatic IRI, focusing on SEC functions.

Methods: In vivo, using a 60-min partial-warm IRI model, mice were treated with SEW2871 or without it (with vehicle). In vitro, isolated SECs pretreated with SEW2871 or without it (with vehicle) were incubated with hydrogen peroxide.

Results: Compared with the IRI + vehicle group, SEW2871 administration significantly improved serum transaminase levels and liver damage, attenuated infiltration of Ly-6G and mouse macrophage antigen-1-positive cells, suppressed the expression of vascular cell adhesion molecule-1 and proinflammatory cytokines in the liver, and enhanced the expressions of endothelial nitric oxide synthase (eNOS) and vascular endothelial (VE) cadherin in the liver (eNOS/β-actin [median]: 0.24 versus 0.53, P = 0.008; VE-cadherin/β-actin [median]: 0.21 versus 0.94, P = 0.008). In vitro, compared with the vehicle group, pretreatment of SECs with SEW2871 significantly increased the expressions of eNOS and VE-cadherin (eNOS/β-actin [median]: 0.22 versus 0.29, P = 0.008; VE-cadherin/β-actin [median]: 0.38 versus 0.67, P = 0.008). As results of investigation of prosurvival signals, SEW2871 significantly increased Akt phosphorylation in SECs and decreased lactate dehydrogenase levels in supernatants of SECs.

Conclusions: These results indicate that S1PR1 agonist induces attenuation of hepatic IRI, which might be provided by preventing SEC damage. S1PR1 may be a therapeutic target for the prevention of early sinusoidal injury after hepatic IRI.

Keywords: Anti-inflammatory action; Endothelial stabilization; Sinusoidal blood flow; Vascular integrity; Vasorelaxation.