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Seko. Vessel Plus 2020;4:22 I http://dx.doi.org/10.20517/2574-1209.2020.14 Page 5 of 7

levels of ORAIP played a role in other complications such as cardiovascular injury and sarcopenia in these
patients.

For diabetic retinopathy, it is thought that vascular endothelial growth factor (VEGF) plays a critical
role in retinal neovascularization and diabetic macular edema. VEGF also plays a protective role against
retinal apoptosis induced by oxidative stress (perhaps due to retinal I/R) [26,27] . We reported that vitreous
body concentrations of ORAIP were significantly increased in diabetic retinopathy, especially proliferative
[12]
diabetic retinopathy, suggesting that ORAIP plays a role in oxidative stress-induced retinal cell injury .
Therefore, the combination of anti-VEGF and anti-ORAIP therapies will be complementary against
ischemic as well as I/R injury in diabetic retinopathy.

Because neurons (especially cerebral neurons) are susceptible to oxidative stress-induced cell injury, the
long-term elevation of plasma ORAIP levels induced by hyperglycemia should injure peripheral neurons as
well.

Atherosclerotic macroangiopathy
DM is often associated with hypertriglyceridemia due to insulin resistance. In addition, hyperglycemia
in DM induces oxidative stress, which facilitates LDL-C oxidation in arterial tissues leading to plaque
formation. Thus, hyperglycemia in DM often causes dyslipidemia, resulting in the development of
atherosclerotic macroangiopathy involving coronary, cerebral, and peripheral arteries. Atherosclerosis in
these large arteries leads to life-threatening ischemic heart disease, cerebral infarction, and arteriosclerosis
obliterans. As mentioned in the “Dyslipidemia and atherosclerosis” section, oxidative stress in arterial
tissues induces ORAIP secretion, which may result in apoptosis of arterial cells leading to plaque rupture.
Further investigations are needed to prove the usefulness of anti-ORAIP therapy with a neutralizing mAb
in protecting from atherosclerotic plaque rupture and cardiovascular injury in patients with DM as well as
dyslipidemia.

Muscle injury
Myocardial injury, as well as sarcopenia, often develops later in the course of DM, causing various types of
arrhythmias (such as atrial fibrillation and paroxysmal supraventricular tachycardia) and heart failure (such
as diabetic cardiomyopathy). Because cardiac and skeletal myocytes are susceptible to oxidative stress-
induced apoptosis mediated by ORAIP, and ORAIP has a critical role in hyperglycemia-induced myocardial
[24]
injury , hyperglycemia-induced high plasma levels of ORAIP may also mediate the development of
sarcopenia.

Taken together, these data offer a possible anti-ORAIP therapy against vascular as well as cardiac and
skeletal muscle injury involved in DM.

CARDIOVASCULAR COMPLICATIONS IN CKD
Cardiovascular complications critically affect the morbidity and mortality of CKD, especially in end-
stage renal disease patients on dialysis. Because conventional cardiovascular risk factors such as DM,
hypertension, hypercholesterolemia, and smoking are often associated with CKD, oxidative stress has
[28]
been implicated in the mechanism of cardiovascular injury in CKD , though the precise mechanism is
still unclear. To investigate the roles of ORAIP in oxidative stress-induced cardiovascular injury in CKD,
we analyzed the plasma levels of ORAIP in patients with the end-stage renal disease just before and after
[9]
dialysis . Plasma ORAIP levels before dialysis were markedly elevated [93.6 ± 5.1 (mean ± SE) ng/mL] as
compared with those of control subjects (6.6 ± 1.5 ng/mL). After dialysis, plasma levels of ORAIP were not
decreased, but rather slightly (and significantly) increased to 98.5 ± 5.7 ng/mL (P = 0.0122), suggesting that
ORAIP may be a little concentrated, but not eliminated by dialysis.