Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury.
Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury.
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DOI：
10.1002/hep.23833
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发表时间：
2010-10
期刊：
影响因子：
13.5
通讯作者：
Morales, Albert
中科院分区：
文献类型：
--
作者：
Llacuna, Laura;Barcena, Cristina;Bellido-Martin, Lola;Fernandez, Laura;Stefanovic, Milica;Mari, Montserrat;Garcia-Ruiz, Carmen;Fernandez-Checa, Jose C.;Garcia de Frutos, Pablo;Morales, Albert
生长停滞特异基因6(Gas6)在不同器官(包括肝脏)的组织修复和发育过程中促进生长和细胞存活。然而，Gas6在肝脏缺血/再灌注(I/R)损伤中的具体作用尚未被阐明。在这里，我们报告了I/R暴露后血清Gas6水平的早期增加。此外，与野生型小鼠不同，Gas6-/-小鼠对部分肝脏I/R高度敏感，90%的小鼠因大量肝细胞损伤而在再灌注12小时内死亡。Gas6-/-小鼠肝脏I/R后早期肝脏AKT磷酸化水平明显高于野生型小鼠，而Gas6-/-小鼠肝组织中IL-1β和TFNmRNA量明显高于野生型小鼠。与体内实验数据一致，体外研究表明，Gas6诱导原代小鼠肝细胞Akt磷酸化，保护其免受缺氧诱导的细胞死亡，而Gas6抑制脂多糖诱导的小鼠巨噬细胞中细胞因子(IL-1β和肿瘤坏死因子)的表达。最后，体内重组Gas6治疗不仅挽救了Gas6基因敲除的小鼠I/R所致的严重肝损伤，还减轻了野生型小鼠I/R后的肝损伤。综上所述，我们的研究结果揭示了Gas6在肝I/R损伤中的新角色，有望成为减轻缺血后肝损伤的潜在治疗靶点。
Growth 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 following I/R exposure. Moreover, unlike wild type mice, Gas6-/- mice were highly sensitive to partial hepatic I/R, with 90% of mice dying within 12 hours of reperfusion due to massive hepatocellular injury. I/R induced early hepatic AKT phosphorylation in wild type but not in Gas6-/- mice, without significant changes in JNK phosphorylation or nuclear NF-κB translocation, whereas hepatic IL-1β and TNF mRNA levels were higher in Gas6-/- mice compared to wild type mice. In line with the in vivo data, in vitro studies indicated that GAS6 induced AKT phosphorylation in primary mouse hepatocytes protecting them from hypoxia-induced cell death, while GAS6 diminished lipopolysaccharide (LPS)-induced cytokine expression (IL-1β and TNF) in murine macrophages. Finally, in vivo recombinant GAS6 treatment not only rescued GAS6 knockout mice from I/R-induced severe liver damage, but also attenuated hepatic damage in wild type mice following I/R. In conclusion, our data uncover GAS6 as a new player in liver I/R injury, emerging as a potential therapeutic target to reduce post-ischemic hepatic damage.
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影响因子：
3.7
作者：
Lluis JM;Llacuna L;von Montfort C;Bárcena C;Enrich C;Morales A;Fernandez-Checa JC
通讯作者：
Fernandez-Checa JC
影响因子：
13.5
作者：
Llacuna, Laura;Marí, Montserrat;Morales, Albert
通讯作者：
Morales, Albert
DOI：
10.1152/ajpheart.00020.2004
发表时间：
2004-09-01
影响因子：
4.8
作者：
Hasanbasic, I;Cuerquis, J;Blostein, MD
通讯作者：
Blostein, MD
影响因子：
3.5
作者：
Nyberg, P;Dahlbäck, B;de Frutos, PG
通讯作者：
de Frutos, PG
影响因子：
25.7
作者：
Lafdil, Fouad;Chobert, Marie-Noele;Brouillet, Arthur
通讯作者：
Brouillet, Arthur