6-Methylnitroarachidonate: A novel esterified nitroalkene that potently inhibits platelet aggregation and exerts cGMP-mediated vascular relaxation

被引:17
作者
Blanco, Fabiana [1 ,2 ]
Ferreira, Ana M. [1 ,3 ]
Lopez, Gloria V. [1 ,4 ]
Bonilla, Lucia [1 ,5 ]
Gonzalez, Mercedes [4 ]
Cerecetto, Hugo [4 ]
Trostchansky, Andres [1 ,5 ]
Rubbo, Homero [1 ,5 ]
机构
[1] Univ Republica, Fac Med, Ctr Free Rad & Biomed Res, Montevideo 11800, Uruguay
[2] Univ Republica, Fac Chem Sci, Dept Biophys, Montevideo 11800, Uruguay
[3] Univ Republica, Fac Med, Dept Immunol, Montevideo 11800, Uruguay
[4] Univ Republica, Fac Chem Sci, Dept Organ Chem, Montevideo 11800, Uruguay
[5] Univ Republica, Fac Med, Dept Biochem, Montevideo 11800, Uruguay
基金
英国惠康基金;
关键词
Nitric oxide; Lipid nitration; Nitro-fatty acids; Nitroarachidonic acid; Methylnitroarachidonate; cGMP; Inflammation; Vasorelaxation; Free radicals; NITRATED FATTY-ACIDS; HUMAN BLOOD-PLASMA; NITRIC-OXIDE; NITROLINOLEIC ACID; ARACHIDONIC-ACID; NITROGEN-DIOXIDE; LINOLEIC-ACID; ANTIINFLAMMATORY PROPERTIES; LIPID-PEROXIDATION; PEROXYNITRITE;
D O I
10.1016/j.freeradbiomed.2010.11.031
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Nitro-fatty acids represent endogenously occurring products of oxidant-induced nitration reactions. We have previously synthesized a mixture of four isomers of nitroarachidonic acid, a novel anti-inflammatory signaling mediator. In this study, we synthesized and chemically and biologically characterized for the first time an esterified nitroalkene derived from the nitration of methylarachidonate (AAMet): 6-methylnitroarachidonate (6-AAMetNO(2)). Synthesis was performed by reacting AAMet with sodium nitrite under acidic conditions. Analysis by mass spectrometry (positive-ion ESI-MS) showed an [M + H](+) ion of m/z 364, characteristic of AAMetNO(2). Fragmentation of this ion yielded a daughter ion at m/z 377, corresponding to the neutral loss of the nitro group ([M + H - HNO2](+)). Furthermore, IR signal at 1378 cm(-1) and NMR data confirmed the structure of a 6-nitro-positional isomer. This novel esterified nitroalkene was capable of promoting vascular protective actions including: (a) the induction of vasorelaxation via endothelium-independent mechanisms. associated with an increase in smooth muscle cell cGMP levels, and (b) a potent dose-dependent inhibition of human platelet aggregation. We postulate that 6-AAMetNO(2) could be a potential drug for the prevention of vascular and inflammatory diseases, and the presence of the methyl group may increase its pharmacological potential. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:411 / 418
页数:8
相关论文
共 44 条
[31]   Acid-promoted reactions of ethyl linoleate with nitrite ions: Formation and structural characterization of isomeric nitroalkene, nitrohydroxy, and novel 3-nitro-1,5-hexadiene and 1,5-dinitro-1,3-pentadiene products [J].
Napolitano, A ;
Camera, E ;
Picardo, M ;
d'Ischia, M .
JOURNAL OF ORGANIC CHEMISTRY, 2000, 65 (16) :4853-4860
[32]   Lipid peroxidation: Physiological levels and dual biological effects [J].
Niki, Etsuo .
FREE RADICAL BIOLOGY AND MEDICINE, 2009, 47 (05) :469-484
[33]   THE NEF REACTION [J].
NOLAND, WE .
CHEMICAL REVIEWS, 1955, 55 (01) :137-155
[34]   Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitrous acid, nitrogen dioxide, and nitronium ion [J].
O'Donnell, VB ;
Eiserich, JP ;
Chumley, PH ;
Jablonsky, MJ ;
Krishna, NR ;
Kirk, M ;
Barnes, S ;
Darley-Usmar, VM ;
Freeman, BA .
CHEMICAL RESEARCH IN TOXICOLOGY, 1999, 12 (01) :83-92
[35]  
RUBBO H, 1994, J BIOL CHEM, V269, P26066
[36]   Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion [J].
Rudolph, Volker ;
Rudolph, Tanja K. ;
Schopfer, Francisco J. ;
Bonacci, Gustavo ;
Woodcock, Steven R. ;
Cole, Marsha P. ;
Baker, Paul R. S. ;
Ramani, Ravi ;
Freeman, Bruce A. .
CARDIOVASCULAR RESEARCH, 2010, 85 (01) :155-166
[37]   Nitro-fatty Acid Metabolome: Saturation, Desaturation, β-Oxidation, and Protein Adduction [J].
Rudolph, Volker ;
Schopfer, Francisco J. ;
Khoo, Nicholas K. H. ;
Rudolph, Tanja K. ;
Cole, Marsha P. ;
Woodcock, Steven R. ;
Bonacci, Gustavo ;
Groeger, Alison L. ;
Golin-Bisello, Franca ;
Chen, Chen-Shan ;
Baker, Paul R. S. ;
Freeman, Bruce A. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (03) :1461-1473
[38]   Nitric oxide-mediated cyclooxygenase activation - A key event in the antiplatelet effects of nitrovasodilators [J].
Salvemini, D ;
Currie, MG ;
Mollace, V .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (11) :2562-2568
[39]   Fatty acid transduction of nitric oxide signaling - Nitrolinoleic acid is a hydrophobically stabilized nitric oxide donor [J].
Schopfer, FJ ;
Baker, PRS ;
Giles, G ;
Chumley, P ;
Batthyany, C ;
Crawford, J ;
Patel, RP ;
Hogg, N ;
Branchaud, BP ;
Lancaster, JR ;
Freeman, BA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (19) :19289-19297
[40]   Nitrolinoleic acid:: An endogenous peroxisome proliferator-activated receptor γ ligand [J].
Schopfer, FJ ;
Lin, YM ;
Baker, PRS ;
Cui, TX ;
Garcia-Barrio, M ;
Zhang, JF ;
Chen, K ;
Chen, YQE ;
Freeman, BA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (07) :2340-2345