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Page 6 of 7 Seko. Vessel Plus 2020;4:22 I http://dx.doi.org/10.20517/2574-1209.2020.14

To assess the effects of high concentrations of plasma ORAIP on the cardiovascular injury, we analyzed
plasma levels of cardiac troponin T and brain natriuretic peptide (BNP). Plasma levels of cardiac troponin
T were considerably elevated and there was a tendency of a positive correlation (but not significant)
[9]
between plasma levels of ORAIP and cardiac troponin T . Because many factors may contribute to
myocardial injury, the absence of a significant positive correlation between plasma levels of ORAIP and
cardiac troponin T does not exclude the possibility that ORAIP may contribute to the myocardial injury.
Plasma BNP levels were markedly elevated. There was also a tendency of a positive correlation (but not
significant and weaker than that for cardiac troponin T) between plasma levels of ORAIP and BNP. This
seems reasonable because cardiac troponin T directly reflects myocardial injury whereas BNP can be
affected by several other factors such as overhydration in patients with end-stage renal disease on dialysis
as well as myocardial injury. Although the primary mechanism of oxidative stress generation in CKD
is unclear, the elevated plasma levels of ORAIP may cause sarcopenia and renal microvascular injury,
resulting in the progression of CKD. Although further in vivo treatment studies are needed, these data
offer support for a possible anti-ORAIP therapy to at least partially protect from cardiovascular injury and
sarcopenia in patients with CKD.

CONCLUSION
For life, oxygen is a double-edged sword because it is not only essential for vital activities, but excessive
oxygen can be harmful to various cells, known as oxidative stress. Since we discovered a novel secreted
form of eIF5A to be ORAIP, we found that plasma levels of ORAIP were elevated in a wide range of acute
and chronic disorders (including cardiovascular diseases), in which oxidative stress is known to be involved
in the pathogenesis. Using animal models of such disorders, we also demonstrated that anti-ORAIP
therapy with neutralizing mAbs could critically reduce oxidative stress-induced cell injury. We speculate
that excessive external stresses involved in various pathological conditions including electromagnetic waves
(such as ionizing radiation and ultraviolet), physicochemical stimuli (such as heat-shock, acidification,
pressure overload, and high osmotic pressure) as well as excessive oxygen (such as ischemia/reperfusion)
may trigger the oxidative stress-sensing mechanism of the cells, which results in the secretion of ORAIP.
Then, secreted ORAIP induces apoptosis of the cells in an autocrine/paracrine fashion, that contributes
to the progression of these disorders. Recently, we identified a cell-surface receptor for ORAIP (that is,
ORAIP-receptor; unpublished data), through which ORAIP transduces the apoptotic signal intracellularly.
[24]
From data of hyperglycemia-induced cell apoptosis , it is strongly suggested that the ORAIP/ORAIP-
receptor pathway mediates a great part of oxidative stress-induced cell injury. Therefore, anti-ORAIP
therapy may be very efficient and effective in combination with conventional therapies against oxidative
stress-mediated cell injury in various disorders, especially cardiovascular diseases.

DECLARATIONS
Authors’ contributions
Seko Y contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
The author declared that there are no conflicts of interest.