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Andrea Aguado et al.
STAT STAT STAT PPAR-RXR HIF NF-?B
-859/-851 -699/-691 -454/-437 -427/-416 -239/-227 -60/-40 69/81 221/233
-780/-772 -632/-611
Figure 9. Structure of human NOX-4 gene promoter. Binding sites for transcription factors involved in NOX-4 expression. Retinoid X
receptor (RXR).
3.2. Role of NOX-derived ROS in vascular remodeling
NOXs are important in physiological processes
including host defense, aging, and cellular homeostasis.
However, the up-regulation of different NOXs, including
NOX-1 and NOX-4, has been implicated in several
cardiovascular diseases such as atherosclerosis,
hypertension, diabetes, isquemia/reperfusion, restenosis or
abdominal aortic aneurisms. Thus, NOX-derived ROS
contribute to the oxidative stress, vascular inflammation,
endothelial dysfunction and vascular remodeling observed
in these cardiovascular pathologies (1, 34, 52-54, 99). The
mechanisms whereby NOX-derived ROS contribute to
altered vessel structure include modulation of cell growth,
apoptosis, migration, inflammation and ECM production
(1, 25). This is based on both in vitro and in vivo studies
using genetically modified animals and experimental
models of hypertension, atherosclerosis, aneurysms and
others. However, although a causal relationship has clearly
been demonstrated in many animal studies, an effective
ROS-modulating therapy still remains to be established by
clinical studies. In addition, despite of the amount of
literature available on this subject, the regulation of
specific NOXs in vascular cells is not completely
understood.
As mentioned, many in vitro studies have demonstrated
the role of oxidative stress as facilitator of different
processes leading to vascular remodeling (26, 41, 50). In
addition, several studies in different animal models, have
demonstrated the key role of ROS from different origins in
vascular remodeling in cardiovascular diseases such as
hypertension. Thus, in stroke-prone SHR, tempol, a SOD
analogue, decreased vascular O2•-concentration, increased
antioxidant status and reduced vascular remodeling
observed in this hypertensive model (100). Accordingly, in
the AngII-infused mouse and deoxycorticosterone acetate-
salt-induced hypertensive rat models, apocynin, a non-
specific NADPH oxidase inhibitor, prevented structural
alterations and collagen deposition (64, 101, 102). Finally, production was blunted in NOX-1y/-. According to these
mito-TEMPO, a mitochondria-targeted SOD mimetic, also
reduced structural alterations induced by AngII infusion
(64). On the other hand, exercise training induces
beneficial effects in the structure and/or mechanics of
resistance arteries in hypertension probably through effects blood pressure and aortic hypertrophy in response to AngII
on oxidative stress (24). In addition, different drugs
(angiotensin-converting-enzyme inhibitors and AngII and
mineralocorticoid receptor blockers) with demonstrated
beneficial effects on vascular remodeling are able to
reduce ROS generation in experimental models and in
138 @Real Academia Nacional de Farmacia. Spain
PPAR-RXR
Exon 1
GC box GC box
GC box
humans with cardiometabolic pathologies (9, 103). Besides
having a role on hypertensive vascular remodeling, ROS
are also involved in vascular remodeling in the context of
other cardiovascular diseases such as abdominal aortic
aneurisms or atherosclerosis and the reader is referred to
excellent reviews on this subject (104, 105).
Regarding the specific NOX isoform involved in
vascular remodeling, genetic manipulation in vitro or in
vivo using transgenic knockout or overexpressing mice
have yielded additional although not conclusive results. It
seems that NOX-1-derived ROS are implicated in
migration of different cell types, such as in VSMCs
stimulated with thrombin, PDGF or bFGF (106, 107).
NOX-1 also plays a role in proliferation since targeting
NOX-1 with antisense or siRNA or genetic deletion in
VSMCs inhibits proliferation induced by different stimuli
(107-109). Similarly, in the wire injury-induced neointima
formation model, both proliferation and apoptosis were
reduced in NOX-1 knockout mice (NOX-1y/-) but there
was little difference in mice overexpressing NOX-1
compared with wild type mice (107). Accordingly,
proliferation and migration were reduced in response to
PDGF in cultured NOX-1y/- VSMCs and increased along
with ECM production in cells overexpressing NOX-1
compared with wild type VSMCs (107), suggesting that
NOX-1 is required for the neointima formation. Several
studies have evaluated the role of NOX-1 in vascular
remodeling in response to AngII. AngII induces VSMC
proliferation and migration as well as carotid artery
hyperplasia in rats via AT1R interaction with NOX-1 (26).
Interestingly, in response to AngII, NOX-1y/- mice showed
a marked reduction in aortic media hypertrophy (110,
111), but this reduction was due to a marked decrease in
ECM accumulation and not in the number of VSMCs since
AngII-induced VSMC proliferation was conserved (110).
Conversely, (112) demonstrated that AngII did elicit
similar hypertrophic response in the thoracic aorta of
NOX-1y/- and NOX-1y/+ mice although superoxide
findings, our group has also demonstrated that AngII plus
IL-1ß induced NOX-1-dependent VSMC migration (72).
Finally, transgenic mice overexpressing NOX-1 in VSMCs
showed markedly greater superoxide production, systolic
than their littermate controls, which were partially reversed
by tempol treatment (52). Altogether, these findings
suggest that cell specific location of NOX-1 might be the
key to modulate hypertrophic vascular remodeling being
NOX-1 from VSMCs of fundamental importance.