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

El pdf del artículo es el manuscrito de autor: PMCID:PMC2947564Growth 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.This work was supported by the Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, by the Instituto de Salud Carlos 111 and Ministry of Science and Innovation of Spain (grants FIS09/00056, FIS07/0193, SAF2009-11417, SAF2008-02199, SAF2006-06780, SAF2004-07539, and 8FU2007-61699/BFI), and by the Research Center for Liver and Pancreatic Diseases (grant P50 AA 11999), which is fended by the US National Institute on Alcohol Abuse and Alcoholism.Peer Reviewe