Impaired caveolin‐1 contributes to hepatic ischemia and reperfusion injury via suppression of sphingosine kinase/sphingosine‐1‐phosphate receptor pathway

Abstract

Caveolae are membrane structure enriched in glycosphingolipid and cholesterol and caveolin‐1 (Cav‐1) has been recognized to be pivotal in ischemic tolerance. Sphingosine‐1‐phosphate (S1P), one of the sphingolipid metabolites, is well known for its anti‐apoptotic properties to counteract against ischemia/reperfusion (I/R) injury and it acts through G protein‐coupled S1P receptors (S1P1‐S1P5). Recently, sphingosine kinases (SphK1 and SphK2) which phosphorylate sphingosine to S1P have been a target to regulate S1P pathway. Here, we investigated the cytoprotective role of Cav‐1 against I/R injury focusing on S1P signaling pathway. Mice underwent partial hepatic ischemia for 60 min followed by reperfusion. Recombinant peptides mimicking Cav‐1 scaffolding domain (CSD, 2.5 mg/kg, i.p.) was administered 1 h prior to ischemia. Ischemia itself reduced hepatic Cav‐1 protein level and this decrease persisted by 1 h of reperfusion. However, this decreased Cav‐1 protein level recovered to basal level 6 h of reperfusion and maintained by 24 h of reperfusion. The loss of caveolae structure and decreased Cav‐1 protein level was restored by CSD 1 h of reperfusion. Cav‐1 induction with CSD attenuated I/R‐induced increases in serum ALT and TNF‐α activity. The levels of SphK1 and Sphk2 mRNA decreased 1 h of reperfusion. CSD attenuated the decrease of SphK1 mRNA level while it did not affect SphK2. At 1 h of reperfusion, the levels of S1P1 and S1P2 mRNA decreased and CSD attenuated the decrease of S1P2 mRNA level while it did not affect S1P1. CSD also decreased phosphorylation of p38 MAPK and JNK. Moreover, I/R resulted in increases of cytochrome c release and apoptotic hepatocytes and CSD attenuated these increases. Our findings suggest that decreased Cav‐1 expression might contribute to hepatic I/R injury through down‐regulation of S1P pathway.