Pitavastatin alters the expression of thrombotic and fibrinolytic proteins in human vascular cells.
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-alpha)-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-alpha-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.
Markle
Ronald A
RA
Center of Vascular Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
Han
Jihong
J
Summers
Barbara D
BD
Yokoyama
Toru
T
Hajjar
Katherine A
KA
Hajjar
David P
DP
Gotto
Antonio M
AM
Nicholson
Andrew C
AC
D000818:Animals; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; D011804:Quinolines; C099252:oxidized low density lipoprotein; D013925:Thromboplastin; D010959:Tissue Plasminogen Activator; C108475:pitavastatin