title: Fatty acid nitroalkenes induce resistance to ischemic cardiac injury by modulating mitochondrial respiration at complex II.
abstract: Nitro-fatty acids (NO2-FA) are metabolic and inflammatory-derived electrophiles that mediate pleiotropic signaling actions. It was hypothesized that NO2-FA would impact mitochondrial redox reactions to induce tissue-protective metabolic shifts in cells. Nitro-oleic acid (OA-NO2) reversibly inhibited complex II-linked respiration in isolated rat heart mitochondria in a pH-dependent manner and suppressed superoxide formation. Nitroalkylation of Fp subunit was determined by BME capture and the site of modification by OA-NO2 defined by mass spectrometric analysis. These effects translated into reduced basal and maximal respiration and favored glycolytic metabolism in H9C2 cardiomyoblasts as assessed by extracellular H(+) and O2 flux analysis. The perfusion of NO2-FA induced acute cardioprotection in an isolated perfused heart ischemia/reperfusion (IR) model as evidenced by significantly higher rate-pressure products. Together these findings indicate that NO2-FA can promote cardioprotection by inducing a shift from respiration to glycolysis and suppressing reactive species formation in the post-ischemic interval.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Koenitzer
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Bonacci
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Woodcock
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Chen-Shan
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Nadiezhda
authors.initials: N
authors.lastname: Cantu-Medellin
authors.affiliation: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Kelley
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: fjs2@pitt.edu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Schopfer
mesh_terms: D000475:Alkenes / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D019069:Cell Respiration; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D032386:Myoblasts, Cardiac / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D013481:Superoxides / Q000378:metabolism
chemical_list: D000475:Alkenes; D002316:Cardiotonic Agents; D005227:Fatty Acids; D009574:Nitro Compounds; D013481:Superoxides; D009569:Nitric Oxide; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III
keywords: Electrophile; Inflammation; Mitochondria; Nitro-fatty acid; Nitroalkene