| AMP-activated protein kinase as a target for preconditioning in transplantation medicine. | |
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MedLine Citation:
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PMID: 20571465 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Graft quality before transplantation is a major factor influencing chronic rejection. Organ preservation and ischemia/reperfusion play an important role in the induction of organ injury. Although both suppression of metabolism by hypothermic preservation and preconditioning before ischemia limit injury, understanding the biochemical signaling pathways will allow us to optimize graft preservation further. Adenosine monophosphate-activated protein kinase (AMPK) is an important enzyme sensing cellular energy balance and regulating downstream signaling pathways, signaling toward an energy-conserving state. In this review, we summarize available literature regarding the protective signaling pathways activated by (hypothermic) ischemia and preconditioning and how they can be activated pharmacologically. Optimizing the graft quality before transplantation improves long-term graft survival. The major factor influencing organ quality is organ preservation, cold storage, currently, being a common practice. Loss of cellular homeostasis, inflammation, and endothelial dysfunction are the major factors inducing injury after cold storage. Adenosine triphosphate depletion and anaerobic metabolism during the cold ischemic period lead to mitochondrial dysfunction, disturbed osmoregulation, and cell death inducing inflammation. Ischemic preconditioning consists of brief periods of ischemia preceding preservation and protects organs against injury because of subsequent ischemia/reperfusion, in which endothelial nitric oxide synthase, nuclear factor-kB, and adenosine play a major role. After conversion of adenosine to AMP, AMPK can be activated, a central kinase involved in sensing cellular [AMP]:[adenosine triphosphate] levels and signaling toward an energy-conserving state. Pharmacologic activation of AMPK demonstrated its ability to activate endothelial nitric oxide synthase and inhibit nuclear factor-kB, thereby limiting endothelial dysfunction and inflammation. Further, studies in knock-out mice lacking ENTDP1 and NT5E (enzymes catalyzing formation and degradation of AMP, respectively) demonstrated a clear protective role for AMP in ischemia/reperfusion. AMPK activation before or during organ preservation might be a promising pharmacologic approach to limit organ injury and maintain graft quality before transplantation. |
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Authors:
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Hjalmar R Bouma; Marlies E Ketelaar; Benito A Yard; Rutger J Ploeg; Robert H Henning |
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Publication Detail:
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Type: Journal Article; Review |
Journal Detail:
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Title: Transplantation Volume: 90 ISSN: 1534-6080 ISO Abbreviation: Transplantation Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-20 Completed Date: 2010-09-15 Revised Date: 2010-12-15 |
Medline Journal Info:
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Nlm Unique ID: 0132144 Medline TA: Transplantation Country: United States |
Other Details:
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Languages: eng Pagination: 353-8 Citation Subset: IM |
Affiliation:
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Department of Clinical Pharmacology, Groningen University Institute of Drug Exploration, University Medical Center Groningen, Groningen, The Netherlands. h.r.bouma@med.umcg.nl |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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metabolism* Adenosine / therapeutic use Animals Calcium / metabolism Cytosol / metabolism Energy Metabolism Graft Rejection / prevention & control Humans Hypoxanthine / metabolism Ischemic Preconditioning / methods* Mice Receptors, Purinergic P1 / physiology Reperfusion Injury / prevention & control Signal Transduction / physiology Sodium-Potassium-Exchanging ATPase / metabolism Transplantation / methods* |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Purinergic P1; 58-61-7/Adenosine; 68-94-0/Hypoxanthine; 7440-70-2/Calcium; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase |
| Comments/Corrections | |
Comment In:
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Transplantation. 2010 Dec 15;90(11):1241; author reply 1242
[PMID:
21119505
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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