The Role of Vascular Adhesion Protein-1 in Metabolic and Atherosclerotic Diseases

• Main Authors: Hung-Yuan Li, 李弘元
• Other Authors: Lee-Ming Chuang
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/86646822468398105942

博士 === 國立臺灣大學 === 臨床醫學研究所 === 98 === The understanding of how metabolic abnormality leads to atherosclerosis remains limited. Vascular adhesion protein-1 (VAP-1) has been shown to participate in inflammation, and can catalyze the breakdown of amines through SSAO activity to produce oxidative stress and advanced glycation end products (AGEs). In this study, we explored if serum VAP-1 could be a biomarker for metabolic and atherosclerotic diseases, and investigated part of the mechanism of atherosclerosis which VAP-1 was involved. In cross-sectional studies including 656 subjects, we found that serum VAP-1 was higher in elderly and in female. Serum VAP-1 was higher in subjects with diabetes and was associated with hemoglobin A1C and fasting glucose levels. In oral glucose challenge test, serum VAP-1 was elevated 30 minutes after glucose ingestion. Besides, serum VAP-1 was higher in subjects with chronic kidney diseases. Serum VAP-1 was positively correlated with albuminuria and was negatively associated with estimated glomerular filtration rate. Taken together, these risk factors for atherosclerosis were correlated with serum VAP-1. We also found a link between serum VAP-1 and carotid intima-medial thickness. The change of serum VAP-1 during oral glucose tolerance test was correlated with systemic oxidative stress, AGEs concentrations, and carotid intima-medial thickness, indicating that hyperglycemia may result in atherosclerosis through its effect on serum VAP-1, oxidative stress and AGEs. We tested the prediction ability of serum VAP-1 in a cohort of type 2 diabetes (N=661). We found that serum VAP-1 can predict 10-year cardiovascular mortality, cancer-related mortality, and all-cause mortality. The incremental prediction ability of serum VAP-1 was comparable to that of age, smoking, serum creatinine, and proteinuria. In the literature, proteins which have important physiologic functions in adipocytes are often expressed in monocyte or macrophage and play important physiologic roles. In present study, we demonstrated that monocyte and macrophage do express VAP-1 by RT-PCR, western blot, flow cytometry, and immunofluorocytochemistry on human peripheral blood monocyte, human THP-1 monocyte, and human THP-1 macrophage. In THP-1 macrophage, VAP-1 mRNA and protein expression were up-regulated on differentiation, suggesting a role of VAP-1 in its maturation or function. Inhibition of SSAO activity by semicarbazide or mofegiline can suppress the adhesion of THP-1 monocyte to fibronectin. During differentiation, the adhesion ability significantly increased 1 hour after PMA induction, when SSAO inhibition can no longer suppress adhesion function. Besides, inhibition of SSAO during differentiation can not affect TNF-α secretion by THP-1 macrophage. In summary, we found that serum VAP-1 was associated with risk factors for atherosclerosis. Serum VAP-1 can predict 10-year cardiovascular, cancer-related, and all-cause mortality. We demonstrated that human monocyte expressed VAP-1, which was up-regulated during differentiation to macrophage, and was involved in its adhesion to fibronectin.