Induction of apoptosis and inhibition of migration of inflammatory and vascular wall cells by cerivastatin.
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.
Kaneider
N C
NC
Division of General Internal Medicine, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
Reinisch
C M
CM
Dunzendorfer
S
S
Meierhofer
C
C
Djanani
A
A
Wiedermann
C J
CJ
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001161:Arteriosclerosis / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010718:Phosphatidylserines / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016897:Respiratory Burst / Q000187:drug effects; D014471:Umbilical Veins
D017304:Annexin A5; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010718:Phosphatidylserines; D011725:Pyridines; C086276:cerivastatin; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases