title: Mitochondrial reactive oxygen species: which ROS signals cardioprotection?
abstract: Mitochondria are the major effectors of cardioprotection by procedures that open the mitochondrial ATP-sensitive potassium channel (mitoKATP), including ischemic and pharmacological preconditioning. MitoKATP opening leads to increased reactive oxygen species (ROS), which then activate a mitoKATP-associated PKCε, which phosphorylates mitoKATP and leaves it in a persistent open state (Costa AD, Garlid KD. Am J Physiol Heart Circ Physiol 295, H874-H882, 2008). The ROS responsible for this effect is not known. The present study focuses on superoxide (O2(·-)), hydrogen peroxide (H2O2), and hydroxyl radical (HO(·)), each of which has been proposed as the signaling ROS. Feedback activation of mitoKATP provides an ideal setting for studying endogenous ROS signaling. Respiring rat heart mitochondria were preincubated with ATP and diazoxide, together with an agent being tested for interference with this process, either by scavenging ROS or by blocking ROS transformations. The mitochondria were then assayed to determine whether or not the persistent phosphorylated open state was achieved. Dimethylsulfoxide (DMSO), dimethylformamide (DMF), deferoxamine, Trolox, and bromoenol lactone each interfered with formation of the ROS-dependent open state. Catalase did not interfere with this step. We also found that DMF blocked cardioprotection by both ischemic preconditioning and diazoxide. The lack of a catalase effect and the inhibitory effects of agents acting downstream of HO(·) excludes H2O2 as the endogenous signaling ROS. Taken together, the results support the conclusion that the ROS message is carried by a downstream product of HO(·) and that it is probably a product of phospholipid oxidation.
authors.affiliation: Department of Biology, Portland State University, Portland, Oregon; and.
authors.forename: Anders O
authors.initials: AO
authors.lastname: Garlid
authors.forename: Martin
authors.initials: M
authors.lastname: Jaburek
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Jacobs
authors.forename: Keith D
authors.initials: KD
authors.lastname: Garlid
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010477:Perfusion; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D010743:Phospholipids; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D013481:Superoxides; D017665:Hydroxyl Radical; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; C497257:Prkce protein, rat; D051744:Protein Kinase C-epsilon
keywords: KATP channels; ROS signaling; cardiac ischemia; cardioprotection; mitochondria; reactive oxygen species
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