Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice

Shu-Huei Wang; Tse-Ya Yu; Feng-Chiao Tsai; Christopher Weston; Mao-Shin Lin; Chi-Sheng Hung; Hsien-Li Kao; Yu-I Li; Montse Solé; Mercedes Unzeta; Yuh-Lien Chen; Lee-Ming Chuang; Hung-Yuan Li

doi:10.1016/j.trsl.2018.03.001

Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice

Shu-Huei Wang, Tse-Ya Yu, Feng-Chiao Tsai, Christopher Weston, Mao-Shin Lin, Chi-Sheng Hung, Hsien-Li Kao, Yu-I Li, Montse Solé, Mercedes Unzeta, Yuh-Lien Chen, Lee-Ming Chuang, Hung-Yuan Li

Immunology and Immunotherapy

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Abstract

Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

Original language	English
Journal	Translational Research
Early online date	27 Mar 2018
DOIs	https://doi.org/10.1016/j.trsl.2018.03.001
Publication status	E-pub ahead of print - 27 Mar 2018

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Wang_et_al_Inhibition_of_semicarbazide-sensitive_Translational_Research_2018
Published in Translational Research on 27/03/2018 DOI: 10.1016/j.trsl.2018.03.001
Accepted author manuscript, 1.8 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

https://www.sciencedirect.com/science/article/pii/S1931524418300434Licence: None: All rights reserved

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Wang, S.-H., Yu, T.-Y., Tsai, F.-C., Weston, C., Lin, M.-S., Hung, C.-S., Kao, H.-L., Li, Y.-I., Solé, M., Unzeta, M., Chen, Y.-L., Chuang, L.-M., & Li, H.-Y. (2018). Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice. Translational Research. Advance online publication. https://doi.org/10.1016/j.trsl.2018.03.001

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title = "Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice",

abstract = "Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.",

author = "Shu-Huei Wang and Tse-Ya Yu and Feng-Chiao Tsai and Christopher Weston and Mao-Shin Lin and Chi-Sheng Hung and Hsien-Li Kao and Yu-I Li and Montse Sol{\'e} and Mercedes Unzeta and Yuh-Lien Chen and Lee-Ming Chuang and Hung-Yuan Li",

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language = "English",

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T1 - Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice

AU - Wang, Shu-Huei

AU - Yu, Tse-Ya

AU - Tsai, Feng-Chiao

AU - Weston, Christopher

AU - Lin, Mao-Shin

AU - Hung, Chi-Sheng

AU - Kao, Hsien-Li

AU - Li, Yu-I

AU - Solé, Montse

AU - Unzeta, Mercedes

AU - Chen, Yuh-Lien

AU - Chuang, Lee-Ming

AU - Li, Hung-Yuan

PY - 2018/3/27

Y1 - 2018/3/27

N2 - Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

AB - Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

U2 - 10.1016/j.trsl.2018.03.001

DO - 10.1016/j.trsl.2018.03.001

M3 - Article

SN - 1931-5244

JO - Translational Research

JF - Translational Research

ER -

Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice

Abstract

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