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

DYSLIPIDEMIA AND ATHEROSCLEROSIS
Oxidative stress plays an important role in the pathogenesis of dyslipidemia. Like other risk factors
for atherosclerosis, such as DM, hypertension, and smoking, it is believed to play a critical role in
[19]
atherosclerotic plaque formation and rupture . According to the low-density lipoprotein cholesterol
(LDL-C) modification hypothesis of atherogenesis, normal plasma LDL-C is modified by oxidative stress
in the arterial wall into oxidized LDL (oxLDL), then bound and taken up through scavenger receptors by
monocytes/macrophages chemoattracted by the oxLDL in the arterial wall. Progressive accumulation of
cholesterol in the monocytes/macrophages turns them into foam cells [20-22] . Then, the accumulation of foam
cells in the arterial lesions leads to atherosclerotic plaque formation. Furthermore, it has been postulated
that plaque rupture is often associated with thrombosis and plays a major role in acute coronary syndrome
and cerebral infarction. However, the precise mechanism of plaque vulnerability leading to rupture has
been unclear.

To investigate whether ORAIP has a role in atherosclerosis, especially in the mechanism of plaque rupture,
we analyzed plasma levels of ORAIP and oxLDL in patients with dyslipidemia as well as heterozygous
familial hypercholesterolemia (HeFH). We also examined the expression of ORAIP and the levels of
oxLDL in atherosclerotic coronary arterial tissues obtained from HeFH patients with a coronary artery
bypass graft. Plasma levels of LDL-C, oxLDL, and ORAIP in HeFH were significantly elevated as compared
with those in dyslipidemia. ORAIP and oxLDL colocalized in the plaque lesion of coronary arteries
from a HeFH patient [unpublished observation]. These findings suggested that high levels of plasma
LDL-C facilitate oxidative stress in the arterial wall which, in turn, induces oxLDL accumulation, plaque
formation, and ORAIP secretion, resulting in arterial cell apoptosis leading to plaque rupture. Although
further investigations are needed, our findings suggest that anti-ORAIP therapy could be a way to reduce
atherosclerotic plaque rupture and cardiovascular injury in patients with dyslipidemia, especially HeFH.

DIABETIC CARDIOVASCULAR COMPLICATIONS
Diabetic cardiovascular complications include microangiopathy, atherosclerotic macroangiopathy, and
muscle injury. There are four main molecular mechanisms implicated in the hyperglycemia-induced cell
injury: increased polyol pathway flux, increased advanced glycation end-product formation, activation of
protein kinase C isoforms, and increased hexosamine pathway flux. All of these mechanisms have been
[23]
proposed to reflect the hyperglycemia-induced overproduction of ROS by the mitochondria . We reported
[24]
previously that plasma ORAIP levels in DM model rats were markedly elevated during the diabetic
phase as compared to the non-diabetic control phase, and that there was a significant positive correlation
between plasma levels of glucose and ORAIP. We also found that high glucose-induced massive apoptosis
of cultured cardiac myocytes, which was largely suppressed by neutralizing anti-ORAIP mAbs in vitro.
Furthermore, recombinant-ORAIP induced the apoptosis of pancreatic ß-cells in vitro. Hyperglycemia
[25]
induces pancreatic ß-cell apoptosis leading to insulin deficiency . These findings strongly suggest that
ORAIP plays a pivotal role in hyperglycemia-induced myocardial injury as well as pancreatic ß-cell injury
in DM. ORAIP may be a biomarker and a critical therapeutic target for myocardial injury and progression
of insulin deficiency due to pancreatic ß-cell injury in patients with DM.

Microangiopathy
Diabetic microangiopathy is often associated with three major complications: nephropathy, retinopathy,
and neuropathy. It is proposed that capillary endothelial cells and glomerular mesangial cells are
preferentially injured by hyperglycemia because these cells cannot reduce the transport of glucose inside
the cell when they are exposed to hyperglycemia . Although we do not have data on whether these cells
[26]
secrete ORAIP in response to hyperglycemia, as we reported previously that plasma levels of ORAIP were
markedly elevated in patients undergoing dialysis largely due to diabetic nephropathy . These elevated
[9]