title: Kir6.2 is not the mitochondrial KATP channel but is required for cardioprotection by ischemic preconditioning.
abstract: ATP-sensitive K(+) (KATP) channels that contain K(+) inward rectifier subunits of the 6.2 isotype (Kir6.2) are important regulators of the cardiac response to ischemia-reperfusion (I/R) injury. Opening of these channels is implicated in the cardioprotective mechanism of ischemic preconditioning (IPC), but debate surrounds the contribution of surface KATP (sKATP) versus mitochondrial KATP (mKATP) channels. While responses to I/R injury and IPC have been examined in Kir6.2(-/-) mice before, breeding methods and other technical obstacles may have confounded interpretations. The aim of this study was to elucidate the role of Kir6.2 in cardioprotection and mKATP activity, using conventionally bred Kir6.2(-/-) mice with wild-type littermates as controls. We found that perfused hearts from Kir6.2(-/-) mice exhibited a normal baseline response to I/R injury, were not protected by IPC, and showed a blunted response to the IPC mimetic drug diazoxide. These data suggest that the loss of IPC in Kir6.2(-/-) hearts is not due to an underlying difference in I/R sensitivity. Furthermore, mKATP channel activity was identical in cardiac mitochondria isolated from wild-type versus Kir6.2(-/-) mice, suggesting no role for Kir6.2 in the mKATP. Collectively, these data indicate that Kir6.2 is required for the full response to IPC or diazoxide but is not involved in mKATP formation.
authors.affiliation: Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Wojtovich
authors.forename: William R
authors.initials: WR
authors.lastname: Urciuoli
authors.forename: Shampa
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Aron B
authors.initials: AB
authors.lastname: Fisher
authors.forename: Keith
authors.initials: K
authors.lastname: Nehrke
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
mesh_terms: D000758:Anesthesia; D000777:Anesthetics; D000818:Animals; D002304:Cardiac Pacing, Artificial; D003981:Diazoxide / Q000494:pharmacology; D004562:Electrocardiography; D000431:Ethanol / Q000031:analogs & derivatives; D006331:Heart Diseases / Q000517:prevention & control*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D013793:Thallium; D014665:Vasodilator Agents / Q000494:pharmacology; D000099161:Kcnj11 Channel
chemical_list: D000777:Anesthetics; D003981:Diazoxide; D000431:Ethanol; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D013793:Thallium; D014665:Vasodilator Agents; D000099161:Kcnj11 Channel; C062527:tribromoethanol
keywords: KATP channel; diazoxide; ischemic preconditioning; mitochondria