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Thrombosis |
Lysophosphatidylcholine Induces Urokinase-Type Plasminogen Activator and Its Receptor in Human Macrophages Partly Through Redox-Sensitive Pathway
From the Department of Cardiovascular Medicine (H.O., K.K., H.D., T.M., S.S., H.Y.) and the Institute of Molecular Embryology and Genetics (H.S.), Kumamoto University School of Medicine, Kumamoto City, Japan, and the Department of Vascular Biology (L.A.M.), The Scripps Research Institute, La Jolla, Calif.
Correspondence to Kiyotaka Kugiyama, MD, PhD, Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto City, 860-8556 Japan. E-mail kiyo{at}gpo.kumamoto-u.ac.jp
Abstract—Urokinase-type plasminogen activator (uPA) and its cell surface receptor (uPAR) have been shown to be expressed in macrophages in atherosclerotic arterial walls, but the regulatory mechanisms of their expression remain unclear. The present study was performed to examine the effects of lysophosphatidylcholine (lysoPC), an important atherogenic lipid, on the expression of uPA and uPAR in human monocyte–derived macrophages. LysoPC upregulated the mRNA expression of uPA and uPAR, and it increased the protein expression of uPA in the culture medium and bound to the cell surface and of uPAR in the particulate fraction of the cells. LysoPC significantly increased the binding of the amino-terminal fragment of uPA to the treated cells and the cell-associated plasminogen activator activity. LysoPC stimulated superoxide anion production and increased intracellular oxidant levels in the cells. The combined incubation with reduced glutathione diethyl ester or N-acetylcysteine, antioxidants, suppressed the upregulation of uPA and uPAR mRNA and the increase in plasminogen activator activity by lysoPC. uPA and uPAR mRNA expression was also induced by the incubation with xanthine and xanthine oxidase, a superoxide anion–generating system. The results suggest that lysoPC increased the expression of uPA and uPAR and their functional activities in human monocyte–derived macrophages, at least in part through a redox-sensitive mechanism. This coordinate increase in the expression of uPA and uPAR in human macrophages by lysoPC could play an important role in plaque formation and disruption, arterial remodeling, and angiogenesis in atherosclerotic arterial walls.
Key Words: atherosclerosis • lysophosphatidylcholine • monocyte-derived macrophages • plasminogen activators • antioxidants
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