Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice.
Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice.
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JNK2 和 iNOS 缺乏可改善心脏死亡小鼠肝移植中的肝损伤和存活率
DOI：
10.1016/j.jhep.2015.02.017
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发表时间：
2015-07
影响因子：
25.7
通讯作者：
Zhong, Zhi
中科院分区：
文献类型：
--
作者：
Liu, Qinlong;Rehman, Hasibur;Krishnasamy, Yasodha;Schnellmann, Rick G.;Lemasters, John J.;Zhong, Zhi
关键词：
纳入心脏死亡供者（CDD）的肝移植将增加供肝的可用性，但由于原发性无功能的风险较高而受到阻碍。在这里，我们试图确定导致CDD肝移植物原发性无功能的机制，目的是制定改善功能和预后的策略，重点关注c- jun - n-末端激酶（JNK）激活和线粒体去极化，这是两种已知的移植物衰竭介质。将野生型、iNOS−/−、JNK1−/−或JNK2−/−小鼠在主动脉夹持45分钟后的肝脏移植到野生型受体中。活体受者活体共聚焦显微镜检测线粒体去极化。野生型CDD肝移植后，移植物iNOS和3-硝基酪氨酸加合物表达增加，但肝内皮细胞NOS表达不变。CDD移植的移植物损伤和功能障碍明显高于非CDD移植。inos缺乏和抑制可减轻CDD移植物的损伤，提高其功能和存活率。JNK1/2和凋亡信号调节激酶-1的激活在野生型CDD移植物中显著增加，而inos缺乏则使其钝化。JNK抑制和jnk2缺乏，而不是jnk1缺乏，减少了CDD移植物的损伤，改善了功能和存活。线粒体去极化和phospho-JNK2与Sab（一种与线粒体通透性转变相关的线粒体蛋白）的结合在CDD中高于非CDD移植物。在CDD移植物中，inos缺乏、JNK抑制和jnk2缺乏都降低了线粒体去极化和ATP消耗。JNK抑制和缺乏没有减少CDD移植物中3-硝基酪氨酸加合物。iNOS-JNK2-Sab通路通过增加线粒体去极化促进CDD移植失败，是改善CDD肝移植肝功能和生存率的一个有吸引力的靶点。
Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Livers explanted from wild-type, iNOS−/−, JNK1−/− or JNK2−/− mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS-deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS-deficiency. JNK inhibition and JNK2-deficiency, but not JNK1-deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS-deficiency, JNK inhibition and JNK2-deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization and is an attractive target to improve liver function and survival in CDD liver transplantation.
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DOI：
10.1196/annals.1420.023
发表时间：
2008-01-01
期刊：
CONTROL AND REGULATION OF TRANSPORT PHENOMENA IN THE CARDIAC SYSTEM
影响因子：
--
作者：
Juhaszova, Magdalena;Wang, Su;Sollott, Steven J.
通讯作者：
Sollott, Steven J.
影响因子：
6.2
作者：
Devey, Luke;Mohr, Elodie;Wigmore, Stephen J.
通讯作者：
Wigmore, Stephen J.
影响因子：
6.2
作者：
Astarcioglu, H;Karademir, S;Astarcioglu, I
通讯作者：
Astarcioglu, I
影响因子：
6.2
作者：
Isobe, M;Katsuramaki, T;Matsuno, T
通讯作者：
Matsuno, T
影响因子：
13.5
作者：
Kim, JS;Ohshima, S;Lemasters, JJ
通讯作者：
Lemasters, JJ