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 mesench ymal cells. Since cerivastatin's pleiotropic effects are poorly investigate d, 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 wit h human umbilical vein endothelial cells and neutrophils. Neutrophil, monoc yte, and vascular smooth muscle cell caspase-3 activity and annexin-V bindi ng were quantified by FIENA and FACS, respectively. Cerivastatin [10 pM to 100 muM] decreased leukocyte chemotaxis towards interleukin-8 or RANTES. Mi gration of cells was completely restored by addition of mevalonic acid. In neutrophils, cerivastatin [100 muM] reduced transendothelial migration, whe reas treatment of endothelial cells failed to affect transmigration. Neutro phil respiratory burst activity was unaffected by cerivastatin. At concentr ations 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 transendot helial migration is due to its effects on neutrophils. In addition to its l ipid-lowering effects, pharmacological properties of cerivastatin may inclu de modulatory actions in leukocytes and mesenchymal cells. (C) 2001 Elsevie r Science Ireland Ltd. All rights reserved.