title: Fluvastatin enhances apoptosis in cytokine-stimulated vascular smooth muscle cells.
abstract: Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to attenuate proliferation of vascular smooth muscle cells (VSMCs) by mechanisms independent of lipid reduction. In the current study, we investigated the effect of lipophilic and hydrophilic statins (fluvastatin and pravastatin) on apoptosis in unstimulated or cytokine-stimulated VSMCs. The presence of apoptosis in rat VSMCs was evaluated by electrophoresis of DNA fragments and 4'6'-diamidine-2'-phenylindole staining and quantified by flow cytometry. Fluvastatin but not pravastatin enhanced apoptosis in interleukin-1beta-stimulated VSMCs. The proapoptotic effect of fluvastatin was fully reversed by mevalonate and geranylgeranyl-pyrophosphate, and partially by farnesyl-pyrophosphate, but not by squalene. Inhibition of the extracellular signal-regulated protein kinase (ERK1/2) pathway significantly increased fluvastatin-enhanced apoptosis, whereas inhibition of the p38-mitogen-activated protein kinase (MAPK) pathway significantly prevented this increase. However, fluvastatin showed no effect on the activity of ERK1/2 and p38-MAPK. Furthermore, fluvastatin-induced apoptosis was inhibited by YVAD-FMK (a caspase-1/interleukin-1beta-converting enzyme-like protease inhibitor) and DEVD-FMK (a caspase-3/CPP32 inhibitor), indicating involvement of an important segment in the apoptosis signaling pathway. These findings suggest that fluvastatin enhances apoptosis in cytokine-stimulated VSMCs and that protein prenylation, MAPK (ERK1/2 and p38-MAPK), and caspases are critically involved in the pathways of fluvastatin-enhanced apoptosis.
authors.affiliation: Division of Cardiology, Organ Replacement Research, Jichi Medical School, Minamikawachi-machi, Tochigi, Japan. masafumi@jichi.ac.jp
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yukiyo
authors.initials: Y
authors.lastname: Ogata
authors.forename: Hitoaki
authors.initials: H
authors.lastname: Okazaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Uichi
authors.initials: U
authors.lastname: Ikeda
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shimada
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D017035:Pravastatin / Q000737:chemistry / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D061945:Caspase Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007375:Interleukin-1; D000077340:Fluvastatin; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D017035:Pravastatin