title: 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation.
abstract: The mechanism by which 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) induce apoptosis in vascular smooth muscle cells (VSMCs) is unknown. In this work, we demonstrate that treatment of VSMCs with simvastatin and atorvastatin inhibited Bcl-2 expression in a time and dose-dependent manner, while Bax expression was not modified. This effect was reversed by mevalonate (100 micromol/l), farnesylpyrophosphate (5 micromol/l) or geranylgeranylpyrophosphate (5 micromol/l), suggesting the involvement of protein prenylation. The treatment of VSMCs with lipophilic statins was associated with decreased prenylation of p-21 Rho A and mevalonate, farnesyl pyrophosphate (F-PP) and geranylgeranyl pyrophosphate (G-PP) reversed prenylation to basal levels. In addition, overexpression of constitutively active Q63L Rho A prevented, at least in part, apoptosis induced by statins and downregulation of Bcl-2. We also investigated the participation of caspases (proteases) in the apoptosis induced by statins. The treatment of VSMCs with lipophilic statins induced activation of the caspase 9, the first caspase of the mitochondrial pathway. Coincubation of VSMCs with the caspase inhibitor ZVAD-fmk (100 micromol/l) significantly inhibited lipophilic statin-induced apoptosis. These findings indicate that the downregulation of Bcl-2 by Rho GTPases mediates statin-induced apoptosis and suggest a new potential mechanism of action for these drugs on the regulation of cell number in the atherosclerotic lesions.
authors.affiliation: Renal and Vascular Laboratory, Vascular Research Laboratory, Instituto de Investigación Médica, Fundación Jimenéz Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Ana
authors.initials: A
authors.lastname: Villa
authors.forename: Mónica
authors.initials: M
authors.lastname: Ortego
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Hernández-Presa
authors.forename: Angel
authors.initials: A
authors.lastname: Pascual
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Plaza
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017368:Protein Prenylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D012717:Sesquiterpenes; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D012717:Sesquiterpenes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D019821:Simvastatin; D020169:Caspases; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid