Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Health Management Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
Transl Res. 2018 Jul;197:12-31. doi: 10.1016/j.trsl.2018.03.001. Epub 2018 Mar 27.
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.
炎症、氧化应激以及晚期糖基化终产物 (AGEs) 和晚期脂氧化终产物 (ALEs) 的形成是动脉粥样硬化的重要因素。血管黏附蛋白-1 (VAP-1) 参与炎症反应，具有半脒基脒敏感胺氧化酶 (SSAO) 活性，可催化氧化脱氨产生过氧化氢和醛，导致 AGEs 和 ALEs 的生成。然而，VAP-1/SSAO 抑制对动脉粥样硬化的影响仍存在争议，并且尚无研究使用冠状动脉造影来评估血浆 VAP-1/SSAO 是否是冠心病 (CAD) 的生物标志物。在这里，我们研究了 VAP-1/SSAO 是否可作为通过冠状动脉造影诊断的 CAD 的生物标志物，并研究了特异性抑制剂 PXS-4728A 对细胞和动物模型中动脉粥样硬化的 VAP-1/SSAO 抑制作用。在该研究中，VAP-1/SSAO 的表达在人类斑块和载脂蛋白 E (ApoE) 缺陷型小鼠的斑块中增加，并且与血管内皮细胞和平滑肌细胞 (SMCs) 共定位。患有 CAD 的患者的血浆 VAP-1/SSAO 高于无 CAD 的患者。血浆 VAP-1/SSAO 与 CAD 的严重程度呈正相关。在 ApoE 缺陷型小鼠中，VAP-1/SSAO 抑制减少了动脉粥样硬化并降低了氧化应激。VAP-1/SSAO 抑制可降低主动脉中黏附分子、趋化因子和促炎细胞因子的表达，并抑制单核细胞黏附和穿过人脐静脉内皮细胞的迁移。因此，VAP-1/SSAO 抑制可减少斑块中巨噬细胞募集和激活的标志物表达。此外，VAP-1/SSAO 抑制抑制 A7r5 SMC 的增殖和迁移。我们的数据表明，血浆 VAP-1/SSAO 是人类 CAD 存在和严重程度的新型生物标志物。PXS-4728A 抑制 VAP-1/SSAO 可能是动脉粥样硬化的潜在治疗方法。
