Pitavastatin alters the expression of thrombotic and fibrinolytic proteins in human vascular cells

• Published in: Journal of cellular biochemistry 2003-09, Vol.90 (1), p.23-32
• Main Authors: Markle, Ronald A., Han, Jihong, Summers, Barbara D., Yokoyama, Toru, Hajjar, Katherine A., Hajjar, David P., Gotto Jr, Antonio M., Nicholson, Andrew C.
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Culture Media, Serum-Free; endothelial cell; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Enzyme Inhibitors - pharmacology; fibrinolysis; Fibrinolysis - physiology; Humans; Lipopolysaccharides - pharmacology; Lipoproteins, LDL - metabolism; monocyte; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Quinolines - pharmacology; smooth muscle; statin; Thromboplastin - genetics; Thromboplastin - metabolism; thrombosis; Thrombosis - metabolism; Tissue Plasminogen Activator - genetics; Tissue Plasminogen Activator - metabolism
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.10602

In addition to lowering blood lipids, clinical benefits of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG Co‐A; EC 1.1.1.34) reductase inhibitors may derive from altered vascular function favoring fibrinolysis over thrombosis. We examined effects of pitavastatin (NK‐104), a relatively novel and long acting statin, on expression of tissue factor (TF) in human monocytes (U‐937), plasminogen activator inhibitor‐1 (PAI‐1), and tissue‐type plasminogen activator (t‐PA) in human aortic smooth muscle cells (SMC) and human umbilical vein endothelial cells (HUVEC). In monocytes, pitavastatin reduced expression of TF protein induced by lipopolysaccharide (LPS) and oxidized low‐density lipoprotein (OxLDL). Similarly, pitavastatin also reduced expression of TF mRNA induced by LPS. Pitavastatin reduced PAI‐1 antigen released from HUVEC under basal, OxLDL‐, or tumor necrosis factor‐alpha (TNF‐α)‐stimulated conditions. Reductions of PAI‐1 mRNA expression correlated with decreased PAI‐1 antigen secretion and PAI‐1 activity as assessed by fibrin–agarose zymography. In addition, pitavastatin decreased PAI‐1 antigen released from OxLDL‐treated and untreated SMC. Conversely, pitavastatin enhanced t‐PA mRNA expression and t‐PA antigen secretion in untreated OxLDL‐, and TNF‐α‐treated HUVEC and untreated SMC. Finally, pitavastatin increased t‐PA activity as assessed by fibrin–agarose zymography. Our findings demonstrate that pitavastatin may alter arterial homeostasis favoring fibrinolysis over thrombosis, thereby reducing risk for thrombi at sites of unstable plaques. J. Cell. Biochem. 90: 23–32, 2003. © 2003 Wiley‐Liss, Inc.