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Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury

AuthorsLlacuna Duran, Laura ; Bárcena, Cristina ; Bellido-Martín, Lola ; Fernández Fernández, Laura ; Stefanovic, Milica ; Marí, Montserrat ; García-Ruiz, Carmen ; Fernández-Checa, José C. ; García de Frutos, Pablo ; Morales, Albert
Issue Date2010
CitationHepatology 52(4): 1371-1379 (2010)
AbstractGrowth arrest specific gene 6 (GAS6) promotes growth and cell survival during tissue repair and development in different organs, including the liver. However, the specific role of GAS6 in liver ischemia/reperfusion (I/R) injury has not been previously addressed. Here we report an early increase in serum GAS6 levels after I/R exposure. Moreover, unlike wild-type (WT) mice, Gas(-/-) mice were highly sensitive to partial hepatic I/R, with 90% of the mice dying within 12 hour; of reperfusion because of massive hepatocellular injury. I/R induced early hepatic protein kinase B (AICT) phosphorylation in WT mice but not in GasC mice without significant changes in c-Jun N-terminal kinase phosphorylation or nuclear factor kappa B translocation, whereas hepatic interleukin-1 beta (IL-1 beta) and tumor necrosis Factor (TNF) messenger RNA levels were higher in Gas6(-/-). mice versus WT mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes and thus protected them from hypoxia-induced cell death, whereas GAS6 diminished fipopolysaccharideinduced cytokine expression (IL-1 beta and TNF) in murine macrophages. Finally, recombinant GAS6 treatment in vivo not only rescued GAS6 knockout mice from severe I/R-induced liver damage but also attenuated hepatic damage in WT mice after I/R. Conclusion: Our data have revealed GAS6 to be a new player in liver I/R injury that is emerging as a potential therapeutic target for reducing postischemic hepatic damage.
DescriptionEl pdf del artículo es el manuscrito de autor: PMCID:PMC2947564
Publisher version (URL)http://dx.doi.org/10.1002/hep.23833
Identifiersissn: 0270-9139
e-issn: 1527-3350
Appears in Collections:(IIBB) Artículos
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