Protective effect of sphingosine-1-phosphate for chronic intermittent hypoxia-induced endothelial cell injury

Highlights: • S1P protect endothelial cells against intermittent hypoxia via Akt/eNOS pathway. • A new dosage form of S1P-MBs may be beneficial in microvascular injury. • The first report of pharmacologic S1P-MBs for pharmacological treatment. Intermittent hypoxia (IH) induced by obstructive sleep apnea (OSA) is the key factor in oxidative stress and the concomitant inflammation of endothelial cells (ECs). In recent years, the lipid sphingosine-1-phosphate (S1P) has been reported to probably play a central role in inflammatory diseases. However, its role in IH-induced endothelial injury remains uncertain. In this study, we investigated the IH-induced ECs inflammation and apoptosis, as well as the role of S1P in both. First, human umbilical vein endothelial cells (HUVECs) were treated with IH to explore the mechanism of S1P and S1P microbubbles (S1P-MBs) in HUVECs with altered function. The intracellular reactive oxygen species (ROS) significantly increased after IH treatment, which further resulted in the increased efficiency of cell apoptosis. Following the S1P and S1P-MBs treatments, the lower Bax protein and Cyt c protein levels in HUVECs indicated the protective effects of S1P for CIH-induced ECs injury. The reason may be that the enhanced expression levels of Gα_(i) and S1P receptor 1 in S1P and S1P-MBs treatment groups could actively increase intracellular p-Akt and p-eNOS protein levels, which counteract the increased ROS secondary to inflammation from IH. Therefore, the Akt/eNOS signaling pathway induced by S1P may be important in protecting IH-induced ECs injury. Furthermore, the S1P-MBs may be designed as a novel S1P dosage formulation to protect the body from the ECs injuries in the future.