ABSTRACT
Statins are thought to play a role in directly affecting immune and mesenchymal cells. Since cerivastatin's pleiotropic effects are poorly investigated, we were interested to find out whether this drug can modulate leukocyte and vessel wall cell functions. Leukocyte migration was tested in modified Boyden microchemotaxis chambers and oxygen radical production was measured fluorometrically. Transendothelial migration experiments were performed with human umbilical vein endothelial cells and neutrophils. Neutrophil, monocyte, and vascular smooth muscle cell caspase-3 activity and annexin-V binding were quantified by FIENA and FACS, respectively. Cerivastatin [10 pM to 100 microM] decreased leukocyte chemotaxis towards interleukin-8 or RANTES. Migration of cells was completely restored by addition of mevalonic acid. In neutrophils, cerivastatin [100 microM] reduced transendothelial migration, whereas treatment of endothelial cells failed to affect transmigration. Neutrophil respiratory burst activity was unaffected by cerivastatin. At concentrations of 10 nM or higher, cerivastatin increased the rate of apoptosis in phagocytes and smooth muscle cells. Results show that cerivastatin is able to inhibit leukocyte chemotaxis, and that cerivastatin induces neutrophil, monocyte, and smooth muscle cell apoptosis. The drug's impact on transendothelial migration is due to its effects on neutrophils. In addition to its lipid-lowering effects, pharmacological properties of cerivastatin may include modulatory actions in leukocytes and mesenchymal cells.
Subject(s)
Apoptosis/drug effects , Endothelium, Vascular/physiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Leukocytes/physiology , Pyridines/pharmacology , Animals , Annexin A5/metabolism , Arteriosclerosis/physiopathology , Caspase 3 , Caspases/metabolism , Cell Division/drug effects , Cell Movement/drug effects , Cells, Cultured , Chemotaxis, Leukocyte/drug effects , Endothelium, Vascular/drug effects , Humans , Leukocytes/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/physiology , Neutrophils/drug effects , Neutrophils/metabolism , Neutrophils/physiology , Phosphatidylserines/metabolism , Rats , Rats, Sprague-Dawley , Respiratory Burst/drug effects , Umbilical VeinsABSTRACT
Resting platelets inhibit oxygen radical release from neutrophils. Antiplatelet therapy may support this function by preventing platelet activation. Whether antiplatelet agents affect the antioxidative action of resting platelets in the absence of platelet activation is unknown. The effect of acetylsalicylic acid or clopidogrel administration on the antioxidative action of resting platelets was therefore studied in ten healthy volunteers. Preparations of resting platelets were obtained from 5 subjects each - before, during and after an eight-day course of daily treatment with 100 mg of acetylsalicylic acid or 75 mg of the thienopyridine clopidogrel. Human peripheral blood neutrophils were pretreated with the platelets at a ratio of (1/5)0 for 45 min; then formyl-Met-Leu-Phe-triggered oxygen radical release was measured fluorometrically. The inhibitory effect of platelets on oxygen radical release from neutrophils which was seen before treatment was abolished by antiplatelet therapy with either of the drugs, and inhibition was restored gradually after discontinuing acetlsalicylic acid/ clopidogrel intake. Results suggest that the protective role of resting platelets in controlling oxygen radical release from neutrophils in the absence of platelet activation may be impaired by antiplatelet therapy.
