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Cervantes-Gracia et al. Vessel Plus 2020;4:27 I http://dx.doi.org/10.20517/2574-1209.2020.22 Page 5 of 19

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Figure 2. Oxidative stress mechanisms in contrast induced nephropathy and cardiovascular disorders. ONOO , OH, O 2 and H 2 O 2 are
physiologically relevant ROS in the vascular endothelium. Processes involved in oxidative stress are represented in bold black. Left side
represent mechanisms described in CVD, right side represent mechanisms described in CIN. Boxes show effects of oxidative stress
in CIN and CVD. Oxidative stress mechanisms lead to inflammation which in turn generates a feedback loop in ROS production. ROS,
NO, and antioxidant enzymes are represented in blue. ⊥: repression/reduction; ↑: overproduction; ↓: decrease; ROS: reactive oxygen
species; NO: nitric oxide; ER: endoplasmic reticulum; ox: oxidases; ETC: electron transfer chain; eNOS: endothelial nitric oxide synthase;
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ONOO : peroxynitrite; OH: hydroxyl radical; O 2 : superoxide anion; H 2 O 2 : hydrogen peroxide; CIN: contrast induced nephropathy; CVD:
cardiovascular disorders
Although an association of these events has been suggested for many years, its interplay remains to be
described. Elucidating the possible interplay between oxidative stress and inflammation is important.

OXIDATIVE STRESS IN CVD AND CIN
ROS play a significant role as second messengers within cells and regulate normal cellular functions,
[99]
including gene transcription, signal transduction and homeostasis . Many sources of ROS exist within
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cells and amongst ROS, the free radical superoxide (O ), is often a proximal ROS. O can lead to
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2
2
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peroxynitrite (ONOO ), hydroxyl radical (OH) and hydrogen peroxide (H O ) production. Univalent
2
2
reduction of molecular oxygen (a diradical) by the mitochondrial electron transport chain (ETC), as well as
by xanthine oxidase, uncoupled endothelial nitric oxide synthase and Nicotinamide adenine dinucleotide
phosphate oxidases (NOXs) leads to O production .
[100]
2
Mitochondria are responsible for the bulk ATP synthesis via chemiosmotic oxidative phosphorylation
(OXPHOS). OXPHOS involves mobile electron carriers shuttles (NADH, cytochrome C and Coenzyme
Q), protein complexes (complexes I-IV and the ATP-synthase complex) and a sequence of redox reactions
where electrons are transported across the complexes of the respiratory chain up to complex IV, where
molecular oxygen is reduced to water. The proton pumps establish an electrochemical proton motive force
necessary for OXPHOS. Mitochondrial ROS can directly disturb the functionality of the ETC complexes by
oxidizing iron-sulfur clusters and protein thiols [Figure 2] [101-103] . Although mitochondria are a major source
for ROS production, no clinical studies have been reported for mitochondrial-targeted antioxidants. This
is largely due to the complications surrounding the targeted antioxidant delivery of injured mitochondria.
Another cause for concern is that the role of mitochondrial ROS differs from cytosolic ROS as they