Document Detail


AMP-activated protein kinase as a target for preconditioning in transplantation medicine.
MedLine Citation:
PMID:  20571465     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Hjalmar R Bouma; Marlies E Ketelaar; Benito A Yard; Rutger J Ploeg; Robert H Henning
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Transplantation     Volume:  90     ISSN:  1534-6080     ISO Abbreviation:  Transplantation     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-20     Completed Date:  2010-09-15     Revised Date:  2010-12-15    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  353-8     Citation Subset:  IM    
Affiliation:
Department of Clinical Pharmacology, Groningen University Institute of Drug Exploration, University Medical Center Groningen, Groningen, The Netherlands. h.r.bouma@med.umcg.nl
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MeSH Terms
Descriptor/Qualifier:
AMP-Activated Protein Kinases / 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:
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:
Transplantation. 2010 Dec 15;90(11):1241; author reply 1242   [PMID:  21119505 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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