Document Detail


Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction.
MedLine Citation:
PMID:  22915766     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury.
METHODS AND RESULTS: CrT-OE mice were selected for left ventricular (LV) creatine 20-100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury.
CONCLUSION: Elevation of myocardial creatine by 20-100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia.
Authors:
Craig A Lygate; Steffen Bohl; Michiel ten Hove; Kiterie M E Faller; Philip J Ostrowski; Sevasti Zervou; Debra J Medway; Dunja Aksentijevic; Liam Sebag-Montefiore; Julie Wallis; Kieran Clarke; Hugh Watkins; Jürgen E Schneider; Stefan Neubauer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-21
Journal Detail:
Title:  Cardiovascular research     Volume:  96     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-04-25     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  466-75     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Creatine / metabolism*
Disease Models, Animal
Energy Metabolism
Glycogen / metabolism
Heart Failure / genetics,  metabolism*,  pathology,  physiopathology
Magnetic Resonance Imaging, Cine
Membrane Transport Proteins / genetics,  metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria, Heart / metabolism
Mitochondrial Membrane Transport Proteins / metabolism
Myocardial Infarction / genetics,  metabolism,  pathology,  physiopathology,  prevention & control*
Myocardial Reperfusion Injury / etiology,  metabolism,  pathology,  physiopathology,  prevention & control*
Myocardial Stunning / metabolism,  pathology,  physiopathology,  prevention & control
Myocardium / metabolism*,  pathology
Necrosis
Oxidative Stress
Phosphocreatine / metabolism
Time Factors
Up-Regulation
Ventricular Function, Left
Ventricular Remodeling
Grant Support
ID/Acronym/Agency:
090532/Z/09/Z//Wellcome Trust; BS/06/001//British Heart Foundation; FS/11/50/29038//British Heart Foundation; PS/02/002/14893//British Heart Foundation; RG/07/004/22659//British Heart Foundation; RG/10/002/28187//British Heart Foundation
Chemical
Reg. No./Substance:
0/Membrane Transport Proteins; 0/Mitochondrial Membrane Transport Proteins; 0/creatine transporter; 0/mitochondrial permeability transition pore; 020IUV4N33/Phosphocreatine; 9005-79-2/Glycogen; MU72812GK0/Creatine
Comments/Corrections

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