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Reactive oxygen species and vascular remodeling in cardiovascular diseases

implicated in cell migration. Depending on the PI3K and EGFR, as well as MAPK, particularly p38
environmental oxidative state these reactions are reversible MAPK, ERK1/2 and ERK5 which as mentioned, have a
or irreversible. Thus, in a reducing environment in the cell key role in cell migration and proliferation and hence in
(normal status) this process is quickly reverted. pathological vascular remodeling (45). These processes
Conversely, in a strongly oxidative environment, the probably occur through oxidation/reduction of protein
sulfenic form is unstable and can undergo further oxidation tyrosine phosphatases (PTP), which are susceptible to
via disproportionation (a type of redox reaction where a oxidation and inactivation by ROS. Increased intracellular
species is simultaneously reduced and oxidized to form ROS also induces an increase in intracellular free calcium
two different products) to sulfinic (-SOH2) species. Under concentration ([Ca2+]i) and an increase in intracellular pH
greater oxidative stress, the sulphonic (-SO3H) species can (pHi) that also contribute to altered contraction and
be created. Other possibilities for post-translational remodeling observed in pathological situations where ROS
cysteine modifications include glutathionylation (-SSG) or have a prominent role (45). Rho GTPases and actin are
the formation of an inter- or intramolecular disulfide bond also sensitive to these modifications leading to actin
(-SS-), thus causing protein oxidative damage (45-47). cytoskeleton reorganization (45, 47, 48). Thus, ROS are
able to induce VSMC proliferation and migration by a
It is also well established, that redox-dependent signaling number of different intracellular signaling pathways
pathways in VSMCs include modifications in the activity (Figure 6).
of protein tyrosine kinases such as Src, Ras, JAK2, Pyk2,

Figure 6. Intracellular mechanisms activated by ROS that participate in cardiovascular disease. NOX-derived ROS activate
different signaling pathways as well as increase in pH and Ca2+. These processes lead to different cellular responses that will end in
cardiovascular disease. Adapted from Briones and Touyz (45).

To date, a number of studies have demonstrated that thus differing from the rest of the ROS-producing enzymes
stimuli important for cardiovascular diseases induce which produce ROS as a by-product of their activity.
VSMC migration and/or proliferation via ROS (49). For NADPH oxidase reduces oxygen to superoxide anion
example, AngII regulates FAT atypical cadherin 1 (Fat1) (O2•-), being NADPH the electron donor; thus, there is an
expression and activity and induces Fat1-dependent electron transfer from the cytosol across biological
VSMC migration via activation of AT1R, ERK1/2, and membranes. There are seven NADPH oxidases isoforms in
NOX-1-derived ROS (50). Similarly, PDGF-induced mammals and all of them have a catalytic subunit called
VSMC migration is ROS dependent and the NOX (NOX-1-5) or DUOX (DUOX-1-2 also called NOX-
Src/PDK1/PAK1 signaling pathway is important as a 6-7) and up to seven regulatory subunits (Figure 7).
ROS-sensitive mediator of migration (51). Moreover, in
VSMCs H2O2 induces cell migration by inducing the NOX-1, NOX-2, NOX-4 and NOX-5 are expressed in
expression of a cytoskeleton protein, ARPC2, through a the cardiovascular system. NOX-2 is the classical NOX
p38 MAPK-dependent mechanism (41) that was primarily characterized in leukocytes. NOX-1,
NOX-2 and NOX-3 activities are regulated by cytosolic
3.1. NADPH oxidases adaptor proteins or “NOX organizers” (p47phox or
NOXO1 and p40phox) and “NOX activators” (p67phox or
As mentioned, NADPH oxidases are the major source NOXA1) that bind GTP-Rac and affect the flow of
of ROS in the vascular wall in physiological and electrons (Figure 7). The p22phox component forms a
pathological conditions (1, 34, 52-54). The main catalytic stable heterodimeric complex with NOX core components
function of NADPH oxidases is the generation of ROS, (NOX-1-4), required for post-translation processing or

@Real Academia Nacional de Farmacia. Spain 135