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rapidly metabolized to water and oxygen by several Andrea Aguado et al.
enzymatic systems such as glutathione peroxidase, catalase
and the thioredoxin system (35, 42, 43) (Figure 5). In the However, an increase in the amount of ROS leads to
presence of transition metals (such as Fe2+) H2O2 can be pathological processes such as endothelial dysfunction,
converted to hydroxyl radicals (HO•), which are highly inflammation and proliferation or migration of VSMCs
reactive and can cause damage to lipids, proteins and leading to vascular remodeling.
DNA. In addition, NO which has a very short half-life, can
react with O2•- to form ONOO- that is capable of The mechanisms responsible of ROS-associated
modifying the structure and function of proteins. Thus, pathological effects are multiple and include quenching of
ROS regulation is important to maintain redox vasodilator NO by O2-., generation of vasoconstrictor lipid
environment of the cell. When there is an imbalance peroxidation products, depletion of BH4, and induction of
between oxidants and antioxidant systems increased ROS fibrosis through activation of matrix metalloproteinases
steady-state levels start multiple pathologies including (45). At intracellular level, ROS induce different processes
inflammation and cardiovascular disease (1, 35). At low such as increased intracellular calcium, activation of
intracellular concentrations, ROS have a key role in the growth and inflammatory transcription factors and
physiological regulation of vascular tone, cell growth, activation of different signaling pathways such as mitogen
adhesion, differentiation, senescence and apoptosis (1, 44). activated protein kinases (MAPK), protein tyrosine
phosphatases, tyrosine kinase, PI3K, and RhoA/ROCK
Mito-ETC (34).

H2O2 SOD3 O2.-
NADPH?Oxidase

ER

e- HO-

O2 O2.- H2O2

SOD2 Fe2+ Xanthine
Mitochondria Oxidase
O2.- ONOO-

SOD1

H2O2

Catalase

H2O +?O2 GSHr NO

H2O +?GSSG NOS
L-arginine
GPR

NADPH NADP-

TRXo TRXr
GRXo GRXr

Figure 5. Reactive oxygen species formation and metabolism. Major sources of ROS generation include the mitochondrial electron
transport chain (Mito-ETC), endoplasmic reticulum (ER) system, NADPH oxidase and xanthine oxidase. Superoxide anion (O2-.) is the
main initial free radical specie which can be converted to other reactive species. In the mitochondria, O2-. is generated by the capture of
electrons escaping from the Mito-ETC by molecular oxygen (O2). O2-. can be rapidly converted to hydrogen peroxide (H2O2) by

superoxide dismutase (SOD), which is caosnFvee2r+t)e,dHto2OH22cOanbybecactoanlavseer,tegdluttoathhyiodnreoxpyelroraxdidicaasles (GPX) or the thioredoxin (TRX) systems. In
the presence of transition metals (such (HO.) NO has a very short half-life and can
react with superoxide to form ONOO-. Glutathione reductase (GPR); glutaredoxin oxidized (GRXo); glutaredoxin reduced (GRXr);

glutathione reduced (GSHr); glutathione oxidized (GSSG); thioredoxin oxidized (TRXo); thioredoxin reduced (TRXr). Adapted from

Trachootham et al. (43).

ROS can act as second messengers activating different methionine and cysteine residues can be targets, the most
intracellular signaling pathways. Particularly, H2O2 important is the cysteine thiol group. ROS react with the
induces post-translational oxidative modifications on sulfur atom of cysteine side chains leading to the
formation of sulfenic acids (-SOH) that can affect proteins
sulfur containing amino acid of proteins. Although

134 @Real Academia Nacional de Farmacia. Spain