title: Caveolin-1 protects against hepatic ischemia/reperfusion injury through ameliorating peroxynitrite-mediated cell death.
abstract: Nitrative stress is considered as an important pathological process of hepatic ischemia and reperfusion injury but its regulating mechanisms are largely unknown. In this study, we tested the hypothesis that caveolin-1 (Cav-1), a plasma membrane scaffolding protein, could be an important cellular signaling against hepatic I/R injury through inhibiting peroxynitrite (ONOO(-))-induced cellular damage. Male wild-type mice and Cav-1 knockout (Cav-1(-/-)) were subjected to 1h hepatic ischemia following 1, 6 and 12h of reperfusion by clipping and releasing portal vessels respectively. Immortalized human hepatocyte cell line (L02) was subjected to 1h hypoxia and 6h reoxygenation and treated with Cav-1 scaffolding domain peptide. The major discoveries included: (1) the expression of Cav-1 in serum and liver tissues of wild-type mice was time-dependently elevated during hepatic ischemia-reperfusion injury. (2) Cav-1 scaffolding domain peptide treatment inhibited cleaved caspase-3 expression in the hypoxia-reoxygenated L02 cells; (3) Cav-1 knockout (Cav-1(-/-)) mice had significantly higher levels of serum transaminases (ALT&AST) and TNF-α, and higher rates of apoptotic cell death in liver tissues than wild-type mice after subjected to 1h hepatic ischemia and 6hour reperfusion; (4) Cav-1(-/-) mice revealed higher expression levels of iNOS, ONOO(-) and 3-nitrotyrosine (3-NT) in the liver than wild-type mice, and Fe-TMPyP, a representative peroxynitrite decomposition catalyst (PDC), remarkably reduced level of ONOO(-) and 3-NT and ameliorated the serum ALT, AST and TNF-α levels in both wild-type and Cav-1(-/-) mice. Taken together, we conclude that Cav-1 could play a critical role in preventing nitrative stress-induced liver damage during hepatic ischemia-reperfusion injury.
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; Research Centre of Heart, Brain, Hormone & Healthy Aging, the University of Hong Kong, Hong Kong, China.
authors.forename: Xingmiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Morningside Laboratory for Chemical Biology and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.affiliation: Morningside Laboratory for Chemical Biology and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.affiliation: Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: lzp48241@126.com.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Lv
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China; Research Centre of Heart, Brain, Hormone & Healthy Aging, the University of Hong Kong, Hong Kong, China; Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. Electronic address: shenjg@hku.hk.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D051242:Caveolin 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009566:Nitrates / Q000378:metabolism / Q000633:toxicity; D030421:Peroxynitrous Acid / Q000378:metabolism / Q000633:toxicity; D011169:Portal Vein / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D051242:Caveolin 1; D009566:Nitrates; D030421:Peroxynitrous Acid; D053148:Caspase 3
keywords: Apoptosis; Caveolin-1; Hepatic ischemia/reperfusion; Peroxynitrite; iNOS