Abstract 10859: Preventive Effects of Neopterin on Atherosclerosis

Introduction: Neopterin, a GTP metabolite produced by activated macrophages after stimulation by interferon-γ released by T cells, is expressed at high levels in the carotid atherosclerotic lesions in patients with angina pectoris. However, the modulatory effect of neopterin on atherogenesis has not yet been reported. Objective and Methods: We aimed to clarify the effects of neopterin on atherogenesis. We investigated the atheroprotective effects of neopterin on human umbilical vein endothelial cells (HUVECs), human monocyte-derived macrophages, human aortic smooth muscle cells (HASMCs) in vitro , and aortic lesions in ApoE -/- mice in vivo . Plasma neopterin levels were compared between 25 patients with acute coronary syndrome (ACS) and 15 healthy volunteers. Results: Neopterin attenuated TNF-α-mediated monocyte adhesion to HUVECs. Neopterin suppressed TNF-α-induced upregulation of MCP-1, ICAM-1, and VCAM-1 in HUVECs. Neopterin shifted the phenotype overwhelmingly to anti-inflammatory M2 rather than inflammatory M1 via NF-κB downregulation during differentiation of human monocytes into macrophages. Neoptein significantly suppressed oxidized LDL-induced foam cell formation associated with reduced CD36 expression and increased both expressions and activities of ABCA1 and ABCG1 in human monocyte-derived macrophages. Neopterin significantly suppressed angiotensin II-induced migration of HASMCs, but increased fibronectin and MMP2 expressions accompanied with enhanced MMP2 activity in HASMCs. Four-week-infusion of neopterin into ApoE -/- mice significantly retarded the development of aortic atherosclerotic lesions with reduced monocyte/macrophage infiltration and lowered plasma levels of total cholesterol. In addition, plasma neopterin levels were markedly increased in ACS patients than healthy volunteers, suggesting that neopterin increased to counteract the formation of atherothrombosis. Conclusions: Our results indicate that neopterin prevents atherogenesis by suppressing monocyte adhesion to endothelial cells, macrophage foam cell formation, and VSMC migration. Thus, neopterin could serve as a novel therapeutic target and potential biomarker for atherosclerotic cardiovascular diseases.