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Page 2 of 7 Seko. Vessel Plus 2020;4:22 I http://dx.doi.org/10.20517/2574-1209.2020.14

ischemia/reperfusion injury, oxidative stress, oxidative stress-responsive apoptosis inducing protein, reactive
oxygen species

INTRODUCTION
Oxidative stress has been strongly implicated in the pathogenesis of various disorders including
cardiovascular diseases, such as arrhythmia, heart failure, dyslipidemia, atherosclerosis, chronic kidney
disease (CKD), diabetic cardiovascular complications, and in particular ischemia/reperfusion (I/R) injury.
Oxidative stress induces reactive oxygen species (ROS) production, lipid peroxidation, protein oxidation,
and DNA damage in the cells that lead to apoptosis. Until recently, ROS were proposed as the key
[1-3]
mediator of oxidative stress-induced cell injury . However, large scale antioxidants (including vitamins,
free radical scavengers) clinical trials have been unsuccessful to improve the outcome of cardiovascular
[4,5]
and cerebrovascular diseases in humans , raising the possibility that there might be some unknown
mechanism other than ROS that mediates oxidative stress-induced cell injury.

In 2015, we reported a novel apoptosis-inducing humoral factor in conditioned medium from cardiac
myocytes subjected to hypoxia/reoxygenation. We reported that this novel secreted form of eukaryotic
translation initiation factor 5A (eIF5A) was sulfated at the 69th tyrosine residue and contained more of
[6]
the hypusinated isoform than the conventional cytosolic form of eIF5A . We found that eIF5A undergoes
tyrosine-sulfation in the trans-Golgi and is rapidly secreted from cardiac myocytes in response to hypoxia/
reoxygenation. It then induces apoptosis by acting as a pro-apoptotic ligand in an autocrine fashion [Figure 1].
We termed this novel tyrosine-sulfated secreted form of eIF5A, Oxidative stress-Responsive Apoptosis-
Inducing Protein (ORAIP) . eIF5A, a member of eIFs regulating the translation initiation step of protein
[6]
synthesis, is the only known protein to contain the unique amino acid hypusine, which is formed post-
translationally via a two-step enzymatic reaction with deoxyhypusine synthase (DHS) and deoxyhypusine
[7]
hydroxylase [Figure 1] . eIF5A is primarily localized to the cytoplasm, where hypusinated eIF5A facilitates
the translation of mRNAs that are involved in cell proliferation. We found that myocardial I/R (but not
ischemia alone) rapidly and markedly increased plasma levels of ORAIP, which returned to the control
level within 60 min. In vivo treatment with an anti-ORAIP neutralizing monoclonal antibody (mAb)
[6]
significantly reduced myocardial I/R injury . It seems that secretion of ORAIP is specific to oxidative
stresses including I/R, hypoxia/reoxygenation, ultraviolet light, ionizing radiation, cold/warm-stress (heat
[8]
shock), and blood acidification , then plays a crucial role in inducing apoptosis of target cells such as
cardiac and skeletal myocytes, neurons, and cancer cells. Especially, these cells need substantial amounts of
oxygen for their activities, making them very sensitive to oxygen concentrations and hence susceptible to
oxidative stress-induced apoptosis mediated by ORAIP.

These results strongly suggested that ORAIP may be a specific biomarker and critical therapeutic target
for oxidative stress-induced cell injury. We also found that the plasma levels of ORAIP were markedly
elevated in patients with chronic disorders such as CKD, atrial fibrillation, heart failure, dyslipidemia,
diabetes mellitus (DM), and diabetic retinopathy, in which oxidative stress plays a critical role in the
pathogenesis [9-12] . Thus, evidence has accumulated that ORAIP may be a common and dominant apoptosis-
inducing ligand among various cell types in response to different types of oxidative stresses involved in a
wide spectrum of acute and chronic disorders, especially cardiovascular diseases.

MYOCARDIAL AND CEREBRAL I/R INJURY
It has been long believed that neutrophils infiltrate into myocardial tissues subjected to I/R and cause
myocardial damage, known as reperfusion injury, due to progressive capillary plugging by neutrophils that
cause capillary no-reflow as well as ROS formation [13-15] . Because reperfusion-induced apoptotic cell death