title: Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion.
abstract: It is believed that biosynthesis of lipid mediators in the central nervous system after cerebral ischemia-reperfusion starts with phospholipid hydrolysis by calcium-dependent phospholipases and is followed by oxygenation of released fatty acids (FAs). Here, we report an alternative pathway whereby cereberal ischemia-reperfusion triggered oxygenation of a mitochondria-specific phospholipid, cardiolipin (CL), is followed by its hydrolysis to yield monolyso-CLs and oxygenated derivatives of fatty (linoleic) acids. We used a model of global cerebral ischemia-reperfusion characterized by 9 minutes of asphyxia leading to asystole followed by cardiopulmonary resuscitation in postnatal day 17 rats. Global ischemia and cardiopulmonary resuscitation resulted in: (1) selective oxidation and hydrolysis of CLs, (2) accumulation of lyso-CLs and oxygenated free FAs, (3) activation of caspase 3/7 in the brain, and (4) motor and cognitive dysfunction. On the basis of these findings, we used a mitochondria targeted nitroxide electron scavenger, which prevented CL oxidation and subsequent hydrolysis, attenuated caspase activation, and improved neurocognitive outcome when administered after cardiac arrest. These data show that calcium-independent CL oxidation and subsequent hydrolysis represent a previously unidentified pathogenic mechanism of brain injury incurred by ischemia-reperfusion and a clinically relevant therapeutic target.
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA [3] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA [4] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA [5] Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ji
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA [3] Medical School at VU Medical Centre, Amsterdam, The Netherlands.
authors.forename: Sophie
authors.initials: S
authors.lastname: Baart
authors.affiliation: 1] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Vikulina
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA [3] Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Robert Sb
authors.initials: RS
authors.lastname: Clark
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA [3] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Tamil S
authors.initials: TS
authors.lastname: Anthonymuthu
authors.affiliation: 1] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tyurin
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.affiliation: 1] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Skoda
authors.affiliation: Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Kline
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA [3] Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: 1] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: 1] Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA [3] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA [4] Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA [5] Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D002561:Cerebrovascular Disorders / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D002308:Cardiolipins