Caveolin-1protects against hepatic ischemia/reperfusion injury through ameliorating peroxynitrite-mediated cell death

Publication date: Available online 25 March 2016
Source:Free Radical Biology and Medicine
Author(s): Lei Gao, Xingmiao Chen, Tao Peng, Dan Yang, Qi Wang, Zhiping Lv, Jiangang Shen
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 miceand Cav-1 knockout (Cav-1^-/-) were subjected to 1hour hepatic ischemia following 1, 6 and 12hours of reperfusion by clipping and releasing portal vessels respectively. Immortalized human hepatocyte cell line (L02) was subjected to 1hour hypoxia and 6hour 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 1hour 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-typeand 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.

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