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Enhanced Recovery from Ischemia Reperfusion Injury in PI3Kα Dominant Negative Hearts: Investigating the Role of Alternate PI3K Isoforms, Increased Glucose Oxidation and MAPK Signaling.
MedLine Citation:
PMID:  23142539     Owner:  NLM     Status:  Publisher    
Classical ischemia reperfusion (IR) preconditioning relies on phosphatidylinositol 3-kinase (PI3K) for protective signaling. Surprisingly, inhibition of PI3Kα activity using a dominant negative (DN) strategy protected the murine heart from IR injury. It has been proposed that increased signaling through PI3Kγ may contribute to the improved recovery of PI3KαDN hearts following IR. To investigate the mechanism by which PI3KαDN hearts are protected from IR injury, we created a double mutant (PI3KDM) model by crossing p110γ(-/-) (PI3KγKO) with cardiac-specific PI3KαDN mice. The PI3KDM model has morphological and hemodynamic features that are characteristic of both PI3Kγ(-/-) and PI3KαDN mice. Interestingly, when subjected to IR using ex vivo Langendorff perfusion, PI3KDM hearts showed significantly enhanced functional recovery when compared to wildtype (WT) hearts. However, signaling downstream of PI3K through Akt and GSK3β, which has been associated with IR protection, was reduced in PI3KDM hearts. Using ex vivo working heart perfusion, we found no difference in functional recovery after IR between PI3KDM and PI3KαDN; also, glucose oxidation rates were significantly increased in PI3KαDN hearts when compared to WT, and this metabolic shift has been associated with enhanced IR recovery. However, we found that PI3KαDN hearts still had enhanced recovery when perfused exclusively with fatty acids (FA). We then investigated parallel signaling pathways, and found that mitogen-activated protein kinase signaling was increased in PI3KαDN hearts, possibly through the inhibition of negative feedback loops downstream of PI3Kα.
Brent A McLean; Petra C Kienesberger; Wang Wang; Grant Masson; Pavel Zhabyeyev; Jason R B Dyck; Gavin Y Oudit
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-7
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  -     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Ltd.
Department of Physiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, Department of Medicine, University of Alberta, Edmonton, Canada.
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