title: Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States; The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Hasibur
authors.initials: H
authors.lastname: Rehman
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Krishnasamy
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States; Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address: zhong@musc.edu.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D003643:Death; D004195:Disease Models, Animal; D006085:Graft Survival; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*
chemical_list: D052247:Nitric Oxide Synthase Type II; D048056:Mitogen-Activated Protein Kinase 9
keywords: Inducible nitric oxide synthase; Liver transplantation; Mitochondrial permeability transition; Non-heart-beating donors; Primary non-function; Sab; c-Jun N-terminal kinase