title: Nitroalkenes confer acute cardioprotection via adenine nucleotide translocase 1.
abstract: Electrophilic nitrated lipids (nitroalkenes) are emerging as an important class of protective cardiovascular signaling molecules. Although species such as nitro-linoleate (LNO(2)) and nitro-oleate can confer acute protection against cardiac ischemic injury, their mechanism of action is unclear. Mild uncoupling of mitochondria is known to be cardioprotective, and adenine nucleotide translocase 1 (ANT1) is a key mediator of mitochondrial uncoupling. ANT1 also contains redox-sensitive cysteines that may be targets for modification by nitroalkenes. Therefore, in this study we tested the hypothesis that nitroalkenes directly modify ANT1 and that nitroalkene-mediated cardioprotection requires ANT1. Using biotin-tagged LNO(2) infused into intact perfused hearts, we obtained mass spectrometric (MALDI-TOF-TOF) evidence for direct modification (nitroalkylation) of ANT1 on cysteine 57. Furthermore, in a cell model of ischemia-reperfusion injury, siRNA knockdown of ANT1 inhibited the cardioprotective effect of LNO(2). Although the molecular mechanism linking ANT1-Cys(57) nitroalkylation and uncoupling is not yet known, these data suggest that ANT1-mediated uncoupling may be a mechanism for nitroalkene-induced cardioprotection.
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.forename: Qiuyu Martin
authors.initials: QM
authors.lastname: Zhu
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Zhu
authors.forename: William
authors.initials: W
authors.lastname: Urciuoli
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000378:metabolism*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D008041:Linoleic Acids / Q000494:pharmacology*; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009574:Nitro Compounds / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
chemical_list: C501855:10-nitro-9,12-octadecadienoic acid; D033741:Adenine Nucleotide Translocator 1; D002316:Cardiotonic Agents; D008041:Linoleic Acids; D009574:Nitro Compounds