The role of vagus nerve stimulation through acetylcholine receptor during　atherosclerosis progression

概要

［課程－２］
審査の結果の要旨
氏名

呉

家賢

This study aimed to evaluate vagus nerve stimulation (VNS) as a therapeutic approach
for atherosclerosis prevention. For the in vivo experiments, long-term VNS was applied
to an atherogenic mouse model (ApoE-KO). GTS-21, a specific agonist of α7 nicotinic
acetylcholine receptor (α7nAChR) was used to stimulate monocytes and endothelial cells
to mimic VNS in vitro. The results are shown below:

1. Long-term VNS reduced body weight and lowered plasma lipid content, including
triglycerides and high-density lipoproteins, in ApoE-KO mice. Unexpectedly, longterm VNS increased atherosclerotic plaque formation in the aorta by an unknown
mechanism.
2. GTS-21 treatment inhibited the mRNA expression level of integrins (SELPLG,
ITGAM, ITGA4) in U-937 cells and its adhesion to endothelial cells. The detailed
mechanism may be by the inhibition of RUNX3, a positive transcriptional regulator
of ITGA4 and ITGAL.
3. GTS-21 treatment inhibited the mRNA expression level of adhesion molecules
(ICAM-1, VCAM-1) in HUVECs and reduced monocyte adhesion on HUVECs.
Using RNA-seq analysis, it was found that a long non-coding RNA called SNGH9
might be involved in this mechanism. Knockdown of SNGH9 in HUVECs showed
profound effects in preventing endothelial dysfunction caused by TNFα treatment,
and reduced their adhesion ability and expression level of adhesion molecules.

In conclusion, this study proves that stimulation of α7nAChR in monocytes or
endothelial cells reduces their adhesion to each other, and molecules RUNX3 and
SNHG9 were found to mediate this adhesion inhibition in monocytes and endothelial
cells, respectively. Additionally, SNHG9 might be a promising therapeutic target for
endothelial dysfunction in vascular diseases. The results of the in vivo experiments, for
the first time, suggest that using VNS in patients with complications such as obesity or
hyperlipidemia may result in similar adverse effects. This research provides a
comprehensive evaluation of the application of VNS to the prevention of atherosclerosis
both in vivo and in vitro and reveals certain underlying mechanisms, which have not
been described by others.
よって本論文は博士（ 医学 ）の学位請求論文として合格と認められる。