title: Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore.
abstract: Aldose reductase (AR), a member of the aldo-keto reductase family, has been demonstrated to play a central role in mediating myocardial ischemia-reperfusion (I/R) injury. Recently, using transgenic mice broadly overexpressing human AR (ARTg), we demonstrated that AR is an important component of myocardial I/R injury and that inhibition of this enzyme protects heart from I/R injury (20-22, 48, 49, 56). To rigorously delineate mechanisms by which AR pathway influences myocardial ischemic injury, we investigated the role played by reactive oxygen species (ROS), antioxidant enzymes, and mitochondrial permeability transition (MPT) pore opening in hearts from ARTg or littermates [wild type (WT)] subjected to I/R. MPT pore opening after I/R was determined using mitochondrial uptake of 2-deoxyglucose ratio, while H2O2 was measured as a key indicator of ROS. Myocardial 2-deoxyglucose uptake ratio and calcium-induced swelling were significantly greater in mitochondria from ARTg mice than in WT mice. Blockade of MPT pore with cyclosphorin A during I/R reduced ischemic injury significantly in ARTg mice hearts. H2O2 measurements indicated mitochondrial ROS generation after I/R was significantly greater in ARTg mitochondria than in WT mice hearts. Furthermore, the levels of antioxidant GSH were significantly reduced in ARTg mitochondria than in WT. Resveratrol treatment or pharmacological blockade of AR significantly reduced ROS generation and MPT pore opening in mitochondria of ARTg mice hearts exposed to I/R stress. This study demonstrates that MPT pore opening is a key event by which AR pathway mediates myocardial I/R injury, and that the MPT pore opening after I/R is triggered, in part, by increases in ROS generation in ARTg mice hearts. Therefore, inhibition of AR pathway protects mitochondria and hence may be a useful adjunct for salvaging ischemic myocardium.
authors.affiliation: Division of Surgical Science , Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: Michiyo
authors.initials: M
authors.lastname: Kaneko
authors.forename: Yuying C
authors.initials: YC
authors.lastname: Hwang
authors.forename: Nosirudeen
authors.initials: N
authors.lastname: Quadri
authors.forename: Teodoro
authors.initials: T
authors.lastname: Gomez
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Casper
authors.initials: C
authors.lastname: Caspersen
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003847:Deoxyglucose / Q000378:metabolism; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D013267:Stilbenes; D016572:Cyclosporine; D003847:Deoxyglucose; D006861:Hydrogen Peroxide; D000449:Aldehyde Reductase; D005978:Glutathione; D000077185:Resveratrol; D002118:Calcium