thromboplastin and pitavastatin

The effects of statins on platelet activation markers, chemokines and adiponectin, were investigated in 135 patients with hyperlipidemia. Of the 135 hyperlipidemic patients, 63 were allocated to the simvastatin group, treated with simvastatin at the dose of 10 mg daily, and the remaining 72 were allocated to the pitavastatin group, treated with pitavastatin at the dose of 2 mg daily. Plasma levels of platelet-derived microparticles (PDMP), cell adhesion molecules (sCD40L and sP-selectin), chemokines [monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normally T-cell expressed and secreted] and adiponectin were measured at the baseline and after 6 months of treatment in both the groups. In addition, we carried out a basic study to investigate the MCP-1-dependent induction of tissue factor expression on a histiocytic cell line (U937 cells). The plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 were higher, whereas those of adiponectin were lower, in the hyperlipidemic patients than in the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, whereas plasma adiponectin was negatively correlated, with the plasma levels of MCP-1. No significant differences in the plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 measured before and after treatment were observed in either the simvastatin or pitavastatin group. A significant increase of the plasma adiponectin levels was observed after 6 months of treatment with pitavastatin but not after an equal duration of treatment with simvastatin. When pitavastatin-treated patients were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases of the plasma MCP-1, PDMP and sCD40L levels were observed after pitavastatin treatment in the responder group. In the aforementioned basic study, MCP-1 by itself did not induce the expression of tissue factor on the U937 cells. However, the recombinant sCD40L-induced expression of tissue factor on U937 was enhanced by the addition of MCP-1. These findings suggest that PDMP, sCD40L and MCP-1 may participate in the development of atherothrombosis in patients with hyperlipidemia and that pitavastatin may exert an adiponectin-dependent antiatherothrombotic effect in hyperlipidemic patients.

Topics: Adiponectin; Adult; Aged; Atherosclerosis; CD40 Ligand; Cell-Derived Microparticles; Chemokine CCL2; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Middle Aged; P-Selectin; Quinolines; T-Lymphocytes; Thrombophilia; Thromboplastin; U937 Cells

Topics: Animals; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Quinolines; Stress, Physiological; Thromboplastin; Up-Regulation

3-hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. The main feature of the antithrombotic properties of endothelial cells is an increase in the expression of thrombomodulin (TM) without induction of tissue factor (TF) expression. We investigated the effect of statins on the expression of TM and TF by endothelial cells.. The incubation of endothelial cells with pitavastatin led to a concentration- and time-dependent increase in cellular TM antigen and mRNA levels. In contrast, the expression of TF mRNA was not induced under the same conditions. A nuclear run-on study revealed that pitavastatin accelerates TM transcription rate. The stimulation of TM expression by pitavastatin was prevented by either mevalonate or geranylgeranylpyrophosphate. Specific inhibition of geranylgeranyltransferase-I and Rac/Cdc42 by GGTI-286 and Clostridium sordellii lethal toxin, respectively, enhanced TM expression, whereas inactivation of Rho by Clostridium botulinum C3 exoenzyme was ineffective.. Statins regulate TM expression via inhibition of small G proteins of the Rho family; Rac/Cdc42. A statin-mediated increase in TM expression by endothelial cells may contribute to the beneficial effects of statins on endothelial function.

Topics: Bacterial Proteins; Bacterial Toxins; Cells, Cultured; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leucine; Mevalonic Acid; Monomeric GTP-Binding Proteins; Polyisoprenyl Phosphates; Quinolines; RNA, Messenger; Thrombomodulin; Thromboplastin; Umbilical Veins; Up-Regulation

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.

Topics: Animals; Cells, Cultured; Culture Media, Serum-Free; Endothelium, Vascular; Enzyme Inhibitors; Fibrinolysis; Humans; Lipopolysaccharides; Lipoproteins, LDL; Monocytes; Myocytes, Smooth Muscle; Plasminogen Activator Inhibitor 1; Quinolines; Thromboplastin; Thrombosis; Tissue Plasminogen Activator