title: Impaired expression of caveolin-1 contributes to hepatic ischemia and reperfusion injury.
abstract: Caveolae are membrane structures enriched in glycosphingolipids 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, counteracting ischemia and reperfusion (IR) injury. Here, we investigated the cytoprotective mechanism of Cav-1 against IR injury. Male C57BL/6 mice underwent 70% hepatic ischemia for 60 min, followed by reperfusion. Mice were pretreated with methyl-beta-cyclodextrin (MβCD, 10, 25 and 50mg/kg, i.p.), a caveolae disruptor, or saline 48 and 24h before ischemia. Serum and liver tissues were collected at the end of ischemia, at 0, 1, 4 and 24h of reperfusion. Decreases in the expression of Cav-1 protein and in the number of caveolae of the liver ultrastructure were observed during IR, which were augmented by pretreatment with MβCD. MβCD also augmented the IR-induced increases in serum alanine aminotransferase and tumor necrosis factor-α levels. IR decreased the levels of sphingosine kinase 2 (SK2) and S1P receptor 2 (S1P2) mRNA expressions, while MβCD also augmented these decreases. Moreover, IR resulted in increases of mitochondrial cytochrome c release, caspase 3, 8 activities and Bax/Bcl-xL ratio, and MβCD augmented all of these apoptotic parameters. MβCD also increased p38 MAPK and JNK phosphorylation, but did not affect ERK and PI3K/Akt. Our findings demonstrate that downregulation of Cav-1 mediates IR-induced liver damage by inhibiting SK2/S1P2 signaling and enhancing the apoptotic pathway.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Kang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: sunmee@skku.edu.
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D051242:Caveolin 1 / Q000378:metabolism*; D017931:DNA Primers; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D017931:DNA Primers; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D013110:Sphingosine
keywords: Apoptosis; Caveolae; Caveolin-1; Ischemia and reperfusion; Sphingosine-1-phosphate