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Watanabe. Vessel Plus 2020;4:4 I http://dx.doi.org/10.20517/2574-1209.2019.27 Page 3 of 10
[10]
[10]
phosphatase 1B (PTP1B) . The PTP1B activation suppresses RAF1 and ERK1/2 phosphorylation .
The activation of PI3K/Akt and/or AMPK suppresses apoptosis of vascular cells (ECs, VSMCs, and
macrophages) and cardiomyocytes. NF-κB and ERK1/2 suppression and AMPK activation inhibit
inflammation, differentiation, migration, and proliferation of the vascular cells; thus, these signalings are
therapeutic targets for atherosclerosis [26-28] . In adipocytes, hepatocytes, and skeletal muscle cells, AMPK
and PPAR-α activation contributes to improving insulin resistance and lipid metabolism, respectively.
AdipoR1 is expressed at high levels in monocytes, macrophages, ECs, VSMCs, cardiomyocytes, adipocytes,
[29]
hepatocytes, and skeletal muscle cells . The AdipoR agonist AdipoRon, an adiponectin-like synthetic
[30]
small molecule, is in the spotlight as an oral anti-atherosclerotic drug .

Several lines of evidence have recently shown the protective effects of osmotin against atherosclerosis,
hyperlipidemia, diabetes, and obesity [10,31-33] . This review article summarizes the therapeutic properties of
osmotin for preventing atherosclerosis and myocardial ischemia-reperfusion injury as well as inflammation
and neurodegeneration. In addition, the article describes the comparisons of the atheroprotective effects
between osmotin and adiponectin or AdipoRon. However, there are no data comparing the exact difference
in the potency of these effects among the three agents.

ATHEROPROTECTIVE EFFECT
In vitro anti-atherosclerotic effects of osmotin
Osmotin has been shown to exert the multiple effects in different cell types including ECs, monocytes/
macrophages, VSMCs, adipocytes, and cardiomyocytes [10,11,33] . The anti-atherosclerotic effects of osmotin
have been investigated using cultured human vascular cells in vitro. In this section, the evidence regarding
the anti-atherosclerotic effects of osmotin is introduced, as summarized in Figure 1.

Preventive effects of osmotin on vascular inflammation
Osmotin suppresses lipopolysaccharide (LPS)-induced upregulation of monocyte chemoattractant protein
1 (MCP1), tumor necrosis factor-α (TNF-α), intercellular adhesion molecule 1 (ICAM1), vascular cell
adhesion molecule 1 (VCAM1), and E-selectin in human umbilical vein endothelial cells (HUVECs) .
[10]
[10]
It suppresses the TNF-α-induced adhesion of human THP1 monocytes to HUVECs . Osmotin shifts
toward an anti-inflammatory phenotype (M2) rather than pro-inflammatory phenotype (M1), associated
with ERK1/2 and NF-κB downregulation and PPAR-γ upregulation in human THP1 monocyte-derived
macrophages . It also suppresses the LPS-induced secretion of interleukin 6 (IL6), pentraxin 3 (PTX3),
[10]
[10]
and TNF-α from human THP1 monocyte-derived macrophages . These findings indicate that osmotin
suppresses vascular inflammation and endothelial dysfunction. In addition, it suppresses the proliferation of
[10]
human EA.hy926 ECs , thus preventing intimal medial thickness. Osmotin mimics the suppressive effects
of adiponectin on the expression of ICAM1, VCAM1, and E-selectin in ECs, monocyte-EC adhesion, and
EC proliferation as well as inflammatory phenotype (M1) and TNF-α expression in macrophages [34-38] .

Preventive effects of osmotin on macrophage foam cell formation
Osmotin suppresses Ox-LDL-induced accumulation of cholesterol ester (foam cell formation) by
downregulating cluster of differentiation 36 (CD36) and acyl-coenzyme A:cholesterol acyltransferase
1 (ACAT1) as well as upregulating ATP-binding cassette transporter A1 (ABCA1) in human THP1
[10]
monocyte-derived macrophages . These effects are consistent with the effects of adiponectin in
suppressing Ox-LDL-induced foam cell formation and ACAT1 expression and enhancing ABCA1
expression in human monocyte-derived macrophages [39-41] .

Preventive effects of osmotin on the migration and proliferation of VSMCs
Osmotin suppresses angiotensin II-induced migration of human aortic smooth muscle cells (HASMCs) .
[10]
It also suppresses the proliferation of HASMCs by decreasing the phosphorylation of RAF1, ERK1/2,