Inhibition of Semicarbazide-sensitive Amine Oxidase Reduces Atherosclerosis in Cholesterol-fed New Zealand White Rabbits

Shu-Huei Wang,Chung-Yi Yang,Lee-Ming Chuang,Feng-Chiao Tsai,Chi-Sheng Hung,Mao-Shin Lin,Yuh-Lien Chen,Hung-Yuan Li,Chien-Yin Su,Tse-Ya Yu,Hsien-Li Kao

doi:10.1038/s41598-018-27551-6

Abstract

Inflammation, oxidative stress, and the formation of advanced glycated end-products (AGEs) are important components of atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation. Its enzymatic activity, semicarbazide-sensitive amine oxidase (SSAO), can catalyze oxidative deamination reactions to produce hydrogen peroxide and aldehydes, leading to the subsequent generation of AGEs. This study aimed to investigate the effect of VAP-1/SSAO inhibition on atherosclerosis. In our study, immunohistochemical staining showed that atherosclerotic plaques displayed higher VAP-1 expression than normal arterial walls in apolipoprotein E-deficient mice, cholesterol-fed New Zealand White rabbits and humans. In cholesterol-fed rabbits, VAP-1 was expressed on endothelial cells and smooth muscle cells in the thickened intima of the aorta. Treatment with PXS-4728A, a selective VAP-1/SSAO inhibitor, in cholesterol-fed rabbits significantly decreased SSAO-specific hydrogen peroxide generation in the aorta and reduced atherosclerotic plaques. VAP-1/SSAO inhibition also lowered blood low-density lipoprotein cholesterol, reduced the expression of adhesion molecules and inflammatory cytokines, suppressed recruitment and activation of macrophages, and decreased migration and proliferation of SMC. In conclusion, VAP-1/SSAO inhibition reduces atherosclerosis and may act through suppression of several important mechanisms for atherosclerosis.

Highlights

Vascular adhesion protein-1 (VAP-1) is an adhesion molecule that is strongly expressed in endothelial cells, smooth muscle cells (SMC), and adipocytes[6,7]
We have demonstrated that VAP-1 expression is higher in atherosclerotic plaques compared to normal arterial walls
Endothelial cells in atherosclerotic plaques displayed stronger VAP-1 expression than those in normal arterial wall, which is consistent with the previous report

Summary

Introduction

Vascular adhesion protein-1 (VAP-1) is an adhesion molecule that is strongly expressed in endothelial cells, smooth muscle cells (SMC), and adipocytes[6,7]. Endothelial VAP-1 is involved in leukocyte rolling, adhesion, and transmigration into inflammatory sites[8] It possesses enzymatic function, semicarbazide-sensitive amine oxidase (SSAO), which catalyzes the oxidative deamination of primary amines (e.g., methylamine, aminoacetone) into aldehydes (formaldehyde, methylglyoxal), hydrogen peroxide, and ammonia[9,10]. The aldehydes can induce endothelial injury through the production of advanced glycation end-products (AGEs) and the cross-linking of proteins to each other[12,13] These effects can result in the development of atherosclerosis. We have shown that serum VAP-1 can predict 10-year cardiovascular mortality in subjects with type 2 diabetes[16] Taken together, these findings suggest that VAP-1/SSAO is involved in the development of atherosclerosis and is a novel target to reduce atherosclerosis. The aim of the present study is to investigate whether a selective VAP-1/SSAO inhibitor (PXS-4728A) can reduce atherosclerosis in cholesterol-fed New Zealand White rabbits and to explore the potential molecular mechanisms

Objectives

Methods

Results

Conclusion