Anti-inflammatory signaling actions of electrophilic nitro-arachidonic
acid in vascular cells and astrocytes
*
Andr
es Trostchansky, Homero Rubbo
*
Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Avda. General Flores 2125, Universidad de la
República, Montevideo 11800, Uruguay
article info
Article history:
Received 22 August 2016
Received in revised form
28 September 2016
Accepted 3 October 2016
Available online xxx
Keywords:
Nitro-arachidonic acid
Lipid nitration
Platelets
Macrophages
Inflammation
Electrophilic signaling
abstract
Nitrated derivatives of unsaturated fatty acids (nitro-fatty acids) are being formed and detected in human
plasma, cell membranes and tissue, triggering signaling cascades via covalent and reversible post-
translational modifications of nucleophilic amino acids in transcriptional regulatory proteins. Arach-
idonic acid (AA) represents a precursor of potent signaling molecules, i.e., prostaglandins and throm-
boxanes through enzymatic and non-enzymatic oxidative pathways. Arachidonic acid can be nitrated by
reactive nitrogen species leading to the formation of nitro-arachidonic acid (NO
2
-AA). A critical issue is
the influence of NO
2
-AA on prostaglandin endoperoxide H synthases, modulating inflammatory pro-
cesses through redirection of AA metabolism and signaling. In this prospective article, we describe the
key chemical and biochemical actions of NO
2
-AA in vascular and astrocytes. This includes the ability of
NO
2
-AA to mediate unique redox signaling anti-inflammatory actions along with its therapeutic
potential.
© 2016 Elsevier Inc. All rights reserved.
1. Introduction
Free as well as esterified fatty acids are important components
of biological membranes that can be modified by reactive oxygen
(ROS) and nitrogen (RNS) species. Nitration of fatty acids is ex-
pected to occur in hydrophobic compartments such as the lipid
bilayer of cellular membranes or the lipophilic core of lipoproteins.
It is well reported that RNS both oxidize and nitrate unsaturated
fatty acids yielding an array of hydroxyl, hydroperoxy, nitro and
nitrohydroxy derivatives [1], with the in vivo mechanism for nitro-
fatty acid (NO
2
-FA) formation still remain unknown. Most of the
available work suggests the presence of nitrogen dioxide (
NO
2
) as
the limiting step, being its most probable source nitric oxide (
NO)
autooxidation [2]. Also,
NO
2
can be generated from the decom-
position of peroxynitrite, peroxidase-catalyzed oxidation of nitrite
(NO
2
) to
NO
2
or reduction of NO
2
in acidic tissue environments
(e.g., gastric compartment, ref. [3]). In fact,
NO and superoxide
radical (O
2
) are the precursors of peroxynitrite which under
inflammatory conditions where it is observed an increase of either
oxidized and nitrated proteins and lipids [4]. Since both perox-
ynitrite and
NO
2
readily diffuse through the membrane bilayers,
reactions leading to
NO
2
generation may take place in the aqueous
environment in proximity to the membrane or inside the lipid
bilayer [5].
Inflammatory related diseases (e.g. atherosclerosis, diabetes)
present an increase of both ROS and RNS formation as well as the
participation of macrophages and platelets in many of the patho-
logical states derived from the activation of inflammatory processes
[6e9]. Both cell types have an active participation of arachidonic
acid (AA) metabolizing pathway with the formation of pro- and
anti-inflammatory eicosanoids as well as formation of ROS and RNS
and changes in the cell redox status [10e13]. The aim of this review
is to discuss the biological effects of the addition of a nitro group
(-NO
2
) to the carbon chain of AA in platelets, macrophages and
astrocytes. Modulation of pro- and anti-inflammatory enzymes by
nitroarachidonic acid (NO
2
-AA) as well as key cellular signaling
pathways are detailed.
1.1. Enzymatic oxidation of arachidonic acid
Arachidonic acid (20:4) is the precursor of many biologically-
and physiologically-relevant bioactive lipids, being its cellular
*
This article is part of a Special Issue entitled The Chemistry of Redox Signaling,
edited by Henry Forman and Willem H. Koppenol.
* Corresponding author. Avda. General Flores 2125, CP 11800, Montevideo,
Uruguay.
E-mail address: hrubbo@fmed.edu.uy (H. Rubbo).
Contents lists available at ScienceDirect
Archives of Biochemistry and Biophysics
journal homepage: www.elsevier.com/locate/yabbi
http://dx.doi.org/10.1016/j.abb.2016.10.003
0003-9861/© 2016 Elsevier Inc. All rights reserved.
Archives of Biochemistry and Biophysics xxx (2016) 1e7
Please cite this article in press as: A. Trostchansky, H. Rubbo, Anti-inflammatory signaling actions of electrophilic nitro-arachidonic acid in
vascular cells and astrocytes, Archives of Biochemistry and Biophysics (2016), http://dx.doi.org/10.1016/j.abb.2016.10.003