TY - JOUR
T1 - Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice
AU - Liu, Qinlong
AU - Rehman, Hasibur
AU - Krishnasamy, Yasodha
AU - Schnellmann, Rick G.
AU - Lemasters, John J.
AU - Zhong, Zhi
N1 - Funding Information:
This study was supported, in part, by Grant DK70844 and DK037034 from the National Institute of Health and Grant #81470878 from Chinese National Natural Foundation. The Cell & Molecular Imaging Core of the Hollings Cancer Center at the Medical University of South Carolina supported by NIH Grant 1P30 CA138313 provided instrumentation and assistance for confocal/multiphoton microscopy. The animals were housed in the Animal Resources at Medical University of South Carolina supported by NIH Grant C06 RR015455.
Funding Information:
This study was supported, in part, by Grant DK70844 and DK037034 from the National Institute of Health and Grant #81470878 from Chinese National Natural Foundation .
Publisher Copyright:
© 2015 European Association for the Study of the Liver.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Background & Aims 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. Methods Livers explanted from wild-type, inducible nitric oxide synthase knockout (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. Results 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. Conclusion 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 recipients.
AB - Background & Aims 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. Methods Livers explanted from wild-type, inducible nitric oxide synthase knockout (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. Results 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. Conclusion 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 recipients.
KW - c-Jun N-terminal kinase
KW - Inducible nitric oxide synthase
KW - Liver transplantation
KW - Mitochondrial permeability transition
KW - Non-heart-beating donors
KW - Primary non-function
KW - Sab
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U2 - 10.1016/j.jhep.2015.02.017
DO - 10.1016/j.jhep.2015.02.017
M3 - Article
C2 - 25703084
AN - SCOPUS:84931561695
SN - 0168-8278
VL - 63
SP - 68
EP - 74
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 1
M1 - 5562
ER -