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Page 6 of 19 Cervantes-Gracia et al. Vessel Plus 2020;4:27 I http://dx.doi.org/10.20517/2574-1209.2020.22

are responsible for intracellular functions, which are maintained at a delicate equilibrium that could be
[104]
negatively influenced by the careless use of antioxidants .

It is understood that ageing is associated with cardiovascular oxidative stress [105] ; tissue vulnerability to
oxidative damage and is likely to be a key contributor in the development of cardiovascular disease [106] .
Direct CM-induced toxicity on renal tubular epithelial cells appears to be a major contributing factor in
CIN. CM induces renal vasoconstriction, through increased adenosine and endothelin-1 secretion, and
diversion of blood flow from the medulla to the cortex [Figure 2]. Consequently, renal blood flow to the
medulla and GFR is reduced, followed by ischemia in the renal medulla [107,108] .

Atherosclerosis is the main cardiovascular disorder in which the association with oxidative stress
became evident. Oxidized low density lipoprotein (oxLDL) plays a critical role in the pathogenesis of
atherosclerosis. Studies have shown a clear link between arterial stiffness and oxLDL concentration,
[109]
independent of the typical CVD risk factors . It remains uncertain whether oxLDL as an oxidative stress
[110]
biomarker has any predictive property in cardiovascular patients .

Vascular NOXs are important ROS generating enzymes and in human vascular cells, NOX1, NOX2, NOX4
and NOX5 are expressed. NOX are transmembrane enzyme complexes with a few regulatory subunits and a
[111]
core catalytic subunit, except for NOX5 . NOX activation results in the generation of O from molecular
2
oxygen by the transfer of electrons from NADPH [112] . NADPH oxidase in humans was thought to be
phox
phox
phagocyte specific as the two membrane bound units, gp91 and p22 form a heterodimer and mediate
bacterial killing by generating O (gp91 phox produces a burst of O and p22 phox acts to stabilize gp91 phox ,
2
2
[113]
phox
enhancing O production) . P22 expression in non-phagocytic cells directed the discovery of NOX1 in
2
[111]
non-phagocytic cells which then led to the identification of the other NOX proteins .
NOX4 plays a key regulatory role, generating athero-protective ROS that inhibits inflammation
and vascular remodeling. Decreased levels of effector T cells and chemokines, increased regulatory
T-cells and reduced lesion formation was seen in apolipoprotein E-deficient mice expressing ectopic
endothelial NOX4 [114] . However, reduced levels of endothelial H O and phosphorylated mothers against
2
2
decapentaplegic homolog 3 (p-SMAD3), along with the elevated expression of profibrotic connective tissue
[115]
growth factor has been seen when NOX4 was downregulated in human aortic endothelial cells . NOX4
knockdown in vivo has also been shown to elevate fibrillar collagens I and III production in plaques, which
[116]
is linked to increased p-SMAD3 levels and transforming growth factor-β expression in diabetic lesions .
During the development of arteriosclerosis, NOX4 and H O regulate the response of EC to endoplasmic
2
2
reticulum (ER) stress [Figure 2] [117] . ER stress leads to elevated ER H O in a NOX4-dependent manner
2
2
which then results in Ras-specific guanine nucleotide releasing factor (RasGRF) activation, the oxidation of
2+
thiols in the Ca -ATPase of sarcoplasmic reticulum microsomes and increased cytosolic calcium levels. In
addition, NOX produced ROS affects X-box-binding protein 1 (KBP1) splicing, a key protein that promotes
[118]
EC apoptosis and atherosclerosis formation .
As well as the increased production of oxLDL, an additional contributor to cardiovascular morbidity
appears to be oxidative endothelial damage. In healthy adults of varying ages, brachial artery flow-mediated
dilation appeared to inversely correlate with the concentration of nitrotyrosine (produced, for example,
[119]
via nitrogen dioxide radical and tyrosine radical recombination) in vascular EC . ET-1, as well as being
a powerful vasoconstrictor, has also demonstrated proinflammatory and prooxidant properties and
[120]
consequently, it has been associated with oxidative endothelial damage . In EC, oxLDL has been shown
to stimulate endothelin-1 production, and elevated levels of endothelin-1 is known to generate ROS by
[121]
NADPH oxidase [Figure 2] . Furthermore, the cardiovascular system inflammatory response is induced
by oxidative stress and proinflammatory cytokines additionally induce oxidative damage in a positive,
[122]
reverse feedback mechanism [Figure 2] .