Signal pathway responsible for hepatocyte preconditioning by nitric oxide
Signal pathway responsible for hepatocyte preconditioning by nitric oxide
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DOI：
10.1016/s0891-5849(03)00039-x
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发表时间：
2003-04-15
影响因子：
7.4
通讯作者：
Albano, E
中科院分区：
文献类型：
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作者：
Carini, R;De Cesaris, MG;Albano, E
一氧化氮（NO）作为肝脏预处理的介质，可提高肝脏对缺氧/再灌注损伤的抵抗力。然而，所涉及的机制仍然知之甚少。在这项研究中，我们研究了短期暴露于NO供体（Z）-1-（N-甲基-N-[6-（N-甲基氨基己基）氨基]）-二氮烯-1-鎓-1，2-二醇盐（NOC-9）增加肝细胞对缺氧损伤耐受性的机制。分离的大鼠肝细胞与NOC-9（0.250 mM）预孵育15分钟变得耐缺氧引起的杀伤。NOC-9的细胞保护作用不涉及蛋白激酶C的活化，而是通过用1H-（1，2，4）-恶二唑并-（4，3）喹喔啉-1-酮（ODQ）（50 μ M）抑制可溶性鸟苷酸环化酶或用KT 5823（5 μ M）抑制cGMP依赖性激酶（cGK）来阻断。相反，cGMP类似物，8Br-cGMP（50 μ M）模拟NOC-9的作用。Western blot分析显示，用NOC-9或8Br-cGMP处理的肝细胞显著增加p38 MAPK的双重磷酸化。抑制鸟苷酸环化酶或cGK可阻断p38 MAPK的激活。NO预处理可显著降低缺氧肝细胞内Na+的积累。KT 5823和p38 MAPK抑制剂SB 203580可逆转这种作用。SB 203580还逆转了NOC-9对缺氧损伤的保护作用。总之，这些结果表明，NO可以通过鸟苷酸环化酶/cGK介导的途径激活p38 MAPK诱导肝预适应。(C)2003年爱思唯尔公司
Nitric oxide (NO) improves liver resistance to hypoxia/reperfusion injury acting as a mediator of hepatic preconditioning. However, the mechanisms involved are still poorly understood. In this study, we have investigated the mechanisms by which short-term exposure to the NO donor (Z)-1-(N-methyl-N-[6-(N-methylammoniohexyl)amino])-diazen-1-ium-1,2-diolate (NOC-9) increases hepatocyte tolerance to hypoxic injury. Isolated rat hepatocytes preincubated 15 min with NOC-9 (0.250 mM) became resistant to the killing caused by hypoxia. NOC-9 cytoprotection did not involve the activation of protein kinase C, but was instead blocked by inhibiting soluble guanylate cyclase with 1H-(1,2,4)-oxadiazolo-(4,3) quinoxalin-1-one (ODQ) (50 muM) or cGMP-dependent kinase (cGK) with KT 5823 (5 muM). Conversely, cGMP analogue, 8Br-cGMP (50 muM) mimicked the effect of NOC-9. Western blot analysis revealed that hepatocyte treatment with NOC-9 or 8Br-cGMP significantly increased dual phosphorylation of p38 MAPK. The activation of p38 MAPK was abolished by inhibiting guanylate cyclase or cGK. Pretreatment with NO significantly reduced intracellular Na+ accumulation in hypoxic hepatocytes. This effect was reverted by KT 5823 as well as by the p38 MAPK inhibitor SB203580. SB203580 also reverted NOC-9 protection against hypoxic injury. Altogether, these results demonstrated that NO can induce hepatic preconditioning by activating p38 MAPK through a guanylate cyclase/cGK-mediated pathway. (C) 2003 Elsevier Inc.