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Reactive oxygen species and vascular remodeling in cardiovascular diseases
Regarding mechanisms activated by NOX-1-derived ROS,
it has been demonstrated that in the presence of some
stimuli, NOX-1 activates different proteins involved in cell
adhesion and migration such as paxilin, Rac, RhoA and
cofilin (44). Moreover, recently NOX-1 has been shown to
be involved in matrix metalloproteinase-9 expression, a
metalloproteinase essential in cell migration since NOX-1
siRNA reduced matrix metalloproteinase-9 expression
(44).
The functional role of NOX-4 in vascular cells is under
debate (54, 56). NOX-4 depletion leads to a loss of
differentiation markers gene expression in adult VSMCs,
while in mouse embryonic stem cells, NOX-4
overexpression increased VSMC differentiation markers
(113, 114). These results suggest that NOX-4 contributes
to the maintenance of a differentiated state of the cell
preventing cell activation or proliferation (44, 54, 113,
115), suggesting a protective effect of NOX-4. However,
transgenic mice with cardiac specific overexpression of
NOX-4 showed decreased left ventricular function with
enhanced O2•-, production in the heart, which was
accompanied by increased apoptosis and fibrosis,
suggesting a deleterious role for NOX-4 (116).
Interestingly, NOX-4-/- mice developed exaggerated
contractile dysfunction, hypertrophy and cardiac dilatation
during exposure to chronic overload, whereas mice with
cardiomyocyte-targeted overexpression of NOX-4 were
protected (117). The different functions of NOX-4 might
also depend on the disease model or stimulus to be studied
(56). In the AngII-infused mouse model, aortas from
NOX-4-deficient animals developed increased
inflammation, media hypertrophy and endothelial
dysfunction compared to their wild type littermates (111)
suggesting that NOX-4 might act as a protective enzyme.
Besides acting on differentiation, proliferation and
migration, NOX-4 has a role in other processes involved in
vascular remodeling such as apoptosis, senescence and cell
cycle (54). Indeed, 7-ketocholesterol-induced apoptotic
events were abolished silencing NOX-4 expression, while
NOX-4 down-regulation inhibited TGF-ß1-dependent cell
proliferation in VSMCs and PASMCs respectively by
regulating ROS production and signaling cascades (81,
118). Thus, it has been suggested that NOX-4 might
regulate fundamental cellular processes that contribute to
each of these responses (54).
Reasons for so different roles for NOX-1 and NOX-4
in vascular biology are far from being clarified. As
mentioned, NOX-4 is a special NOX because it has a high
constitutive activity, is highly expressed in some cells such
as endothelial cells and its subcellular location is different
to other NOXs (56). Moreover, different from NOX-1 and
NOX-2, NOX-4 releases predominantly H2O2. Although
not extensively studied, H2O2 in the media and endothelial
layers may have different functions. Thus, smooth muscle-
specific catalase overexpression blocks the H2O2-mediated
AngII-induced vascular hypertrophy (119) whereas
endothelial-specific catalase overexpression prevents
exercise-stimulated induction of eNOS (120). Future
@Real Academia Nacional de Farmacia. Spain
studies with improved tools will reveal the true nature of
the role of NOX-4 in both health and disease (56).
4. CONCLUSSIONS AND PERSPECTIVES
ROS production in the vasculature by vascular and
non-vascular cells is a highly regulated process. ROS act
as signaling molecules, mainly through oxidative
modification of proteins and subsequent activation or
inhibition of different proteins involved in different
processes including cell signaling or gene transcription. In
cardiovascular diseases, ROS contribute to vascular injury
by promoting among other processes vascular cell growth,
migration, ECM protein deposition, activation of matrix
metalloproteinases or inflammation, which in turn will
favor vascular remodeling. The NADPH oxidase family, is
an important source of ROS in the arterial wall during
cardiovascular diseases and modulate vascular remodeling.
As for the specific NOX isoform NOX-1 and NOX-4 seem
to be particularly important, however, it is well known that
activation of other NOXs (NOX-2 and NOX-5) also
contribute to O2•- production in rodent and/or human
VSMCs (54). The above findings suggest that strategies to
reduce ROS may have therapeutic potential in
cardiovascular alterations in patients. However, results in
humans on this aspect have been not clarifying (34). It has
been proposed that prevention of ROS generation using
specific inhibitors of ROS producing enzymes such as
those of the NADPH oxidase family may be better to
reduce oxidative stress than attempting to scavenge ROS
once they have generated (1). However, to date no
selective inhibitors of NOX that can be used in clinics
have been developed. Long-term awaited studies are
necessary to know if such strategies would be useful in
vascular remodeling associated to cardiovascular diseases.
5. ACKNOWLEDGEMENTS
Studies performed by the authors were supported by
grants from Ministerio de Economía y Competitividad
(SAF2012-36400), Instituto de Salud Carlos III (Red
Investigación Cardiovascular RD12/0042/0024,
PI13/01488) and COST BM1301. AA, MSA and AMB
were supported by a FPI and FPU fellowship and the
Ramón y Cajal program (RYC-2010-06473), respectively.
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