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

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.

Serum vascular adhesion protein-1 predicts all-cause mortality and cancer-related mortality in subjects with colorectal cancer.

BACKGROUND: Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 can predict cancer mortality, including colorectal cancer (CRC) mortality, in type 2 diabetic subjects. However, it remains unknown if serum VAP-1 can predict mortality in CRC patients. This prospective cohort study investigates if serum VAP-1 is a novel biomarker for mortality prediction in CRC. METHODS: We enrolled 300 CRC patients. Preoperative serum VAP-1 was measured by time-resolved immunofluorometric assay. They were followed until September 2009 or death, which was ascertained by the National Death Registration System. RESULTS: The median follow-up period was 4.7 years. Compared with normal counterpart, VAP-1 immunoactivity was upregulated in CRC tissues, especially at the invasion front. Serum VAP-1 can independently predict all-cause mortality (HR: 1.0026, 95% CI: 1.0003-1.0050, P<0.05) and cancer-related mortality (HR: 1.0026, 95% CI: 1.0001-1.0050, P<0.05). A risk score composed of age, gender, carcinoembryonic antigen (CEA) >5 ng/ml, tumor grading, tumor staging, and serum VAP-1 could stratify CRC patients into low-, intermediate-, and high-risk subgroups, with a 5-year mortality rate of 10%, 34%, and 78%, respectively. CONCLUSIONS: Serum VAP-1 predicts mortality independently and improves risk stratification in CRC subjects.

Change of serum vascular adhesion protein-1 after glucose loading correlates to carotid intima-medial thickness in non-diabetic subjects.

BACKGROUND: We investigated if serum vascular adhesion protein-1 (SSAO/VAP-1) changed acutely following oral glucose loading and whether such changes are correlated with surrogate markers of atherosclerosis. METHODS: A total of 115 non-diabetics subjects were enrolled for an oral glucose tolerance test (OGTT). Carotid intima-medial thickness (IMT) was measured by ultrasonography. Serum SSAO/VAP-1 was analyzed by time-resolved immunofluorometric assay. Serum thiobarbituric acid reactive substances (TBARS) and advanced glycated end products (AGEs) were measured by fluorometric assays. RESULTS: Serum SSAO/VAP-1 increased significantly at 30 min after oral glucose loading and lasted to 2 h (p=0.0005 and p<0.0001, for 30 min and 2 h respectively). The area under curve of serum SSAO/VAP-1 during OGTT (AUC-VAP-1) correlated significantly with carotid IMT, independent of age, gender, low-density lipoprotein cholesterol, systolic blood pressure, hemoglobin A1c, serum TBARS, AGEs, and high-sensitivity C-reactive protein. Subjects with a positive AUC-VAP-1 had significantly higher serum TBARS and AGEs than subjects with a negative AUC-VAP-1 adjusted for age and gender. CONCLUSIONS: Serum SSAO/VAP-1 changed acutely following oral glucose loading in non-diabetic subjects. Change of serum SSAO/VAP-1 correlated independently to serum TBARS, AGEs, and carotid IMT. Our findings suggest that acute change of serum SSAO/VAP-1 is a novel marker for hyperglycemia-induced atherosclerosis.