title: Enhanced recovery from ischemia-reperfusion injury in PI3Kα dominant negative hearts: investigating the role of alternate PI3K isoforms, increased glucose oxidation and MAPK signaling.
abstract: 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.
authors.affiliation: Department of Physiology, Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: Brent A
authors.initials: BA
authors.lastname: McLean
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kienesberger
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Grant
authors.initials: G
authors.lastname: Masson
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006339:Heart Rate; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015290:Second Messenger Systems; D017725:Ventricular Pressure
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP; D005947:Glucose; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C546639:Pik3ca protein, mouse; C546764:Pik3cg protein, mouse; C000605507:Gsk3b protein, mouse