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Page 2 of 10 Watanabe. Vessel Plus 2020;4:4 I http://dx.doi.org/10.20517/2574-1209.2019.27

Keywords: Osmotin, atherosclerosis, inflammation, diabetes, obesity, phytochemical, vascular cells, animal models

INTRODUCTION
Atherosclerosis is clinically manifested as coronary artery disease, stroke, and peripheral arterial disease,
[1]
which are major causes of mortality and morbidity worldwide . Atherosclerosis is a chronic inflammatory
vascular disease induced by endothelial injury followed by atheromatous plaque formation, leading to
thickening and loss of elasticity in the arterial wall of medium- and large-sized arteries, including the
[2]
coronary, cerebral, and carotid arteries and the aorta . Risk factors of atherosclerosis include dyslipidemia,
diabetes, obesity, and hypertension. The pathophysiology of atheromatous plaque development involves
endothelial cell (EC) inflammation and proliferation, monocyte adhesion to ECs and infiltration into the
under-endothelial space, inflammatory cytokine release from monocyte-derived macrophages, oxidized
low-density lipoprotein (Ox-LDL)-induced macrophage foam cell formation, vascular smooth muscle
[3]
cell (VSMC) migration and proliferation, and extracellular matrix (ECM) production by VSMCs .
The progression and rupture of atheromatous plaques in coronary arteries lead to myocardial ischemia
and infarction. Timely reperfusion is critical for the salvage of ischemic myocardium. After coronary
angioplasty, restoration of blood flow to the damaged myocardium triggers further ischemic myocardial
damage. This paradoxical phenomenon is known as ischemia-reperfusion injury, which is a serious
clinical problem in the treatment of patients with coronary artery disease. Several studies have investigated
[4-9]
preventive effects of plants on atherogenesis . Osmotin, a plant-derived natural protein, is receiving the
most attention as a therapeutic target for atherosclerosis and myocardial ischemia-reperfusion injury [10,11] .

[12]
Osmotin was first isolated from tobacco (Nicotiana tabacum) cells by Singh et al. . Later, osmotin was
also found in other plant species, including tomato, potato, oat, pepper, and grape . Osmotin is a plant
[13]
peptide hormone, also called phytochemical, which belongs to the fifth class of the group of pathogenesis-
related proteins . The osmotin gene AP24 is known to be activated by environmental and phytohormone
[14]
[15]
signals . Osmotin plays an important role in the protection against osmotic and oxidative stresses caused
[16]
by higher salt concentration, cold, and drought , and has anti-fungal activity in plants . In plants and
[17]
yeasts, osmotin exhibits anti-fungal, anti-oxidant, and anti-apoptotic effects through PHO36, which is an
adiponectin receptor (AdipoR) homolog [13,18] .
Osmotin has recently attracted attention as a homolog of mammalian adiponectin [13,18] , which is the
most famous adipocytokine (adipokine) with anti-inflammatory, anti-diabetic, and anti-atherogenic
properties [19-21] . Osmotin is composed of 246 amino acids including a 21-amino acid signal peptide, which
do not share remarkable similarity to human adiponectin (AdipoQ, 244 amino acids) in the amino acid
[13]
sequence alignment . However, the domain I of osmotin is demonstrated to overlap with the β-barrel
domain of AdipoQ by three-dimensional structure analyses [13,18] ; thereby, osmotin binds to AdipoR1 and
then leads to intracellular signaling [18,22,23] . Therefore, osmotin is regarded as a natural agonist for human
[22]
AdipoR1 . Osmotin exhibits anti-inflammatory and anti-apoptotic effects in mammalian cells through
[10]
AdipoR1 [24,25] . Takahashi et al. recently showed that osmotin exerts atheroprotective effects through human
AdipoR1 in human vascular cells. In intracellular signaling pathways, both nuclear factor-κB (NF-κB)
and extracellular signal-regulated protein kinase 1/2 (ERK1/2) suppression and AMP-activated protein
kinase (AMPK) activation play a pivotal role in the preventive effects of osmotin on inflammation and
atherosclerosis .
[10]

Osmotin as well as adiponectin binds to AdipoR1, leading to the activation of adaptor protein,
phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) followed by phosphoinositide
3-kinase (PI3K)/Akt, AMPK, peroxisome proliferator-activated receptor-α (PPAR-α), and protein-tyrosine