title: 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture.
abstract: Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesions. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to induce apoptosis in a variety of tumor cell lines. To evaluate whether these agents also induce apoptosis of VSMCs, cultured rat VSMCs were treated with increasing doses of atorvastatin in the presence of FBS as a survival factor. The presence of apoptosis was evaluated by morphological criteria, annexin V binding, and DNA fragmentation and quantified as the proportion of hypodiploid cells by flow cytometry. Atorvastatin induced apoptosis in a dose-dependent manner, an effect also seen with simvastatin and lovastatin, but not with the hydrophilic drug pravastatin. The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterols was >95% and was fully reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate but not by isopentenyl adenosine, ubiquinone, or squalene, suggesting a role for prenylated proteins in the regulation of VSMC apoptosis. To further assess the role of protein prenylation, VSMCs were exposed to the prenyl transferase inhibitors perillic acid and manumycin A. Both agents induced VSMC apoptosis as evaluated by the above-mentioned criteria. Finally, VSMC treatment with lipophilic statins was associated with decreased prenylation of p21-Rho B, further supporting the role of protein prenylation inhibition in statin-induced VSMC apoptosis. The present data suggest that interference with protein prenylation by HMG-CoA reductase inhibitors or other agents may provide new strategies for the prevention of neointimal thickening.
authors.affiliation: Instituto de Investigación Médica, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Guijarro
authors.forename: L M
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: M
authors.initials: M
authors.lastname: Ortego
authors.forename: C
authors.initials: C
authors.lastname: Alonso
authors.forename: A
authors.initials: A
authors.lastname: Ortiz
authors.forename: J J
authors.initials: JJ
authors.lastname: Plaza
authors.forename: C
authors.initials: C
authors.lastname: Díaz
authors.forename: G
authors.initials: G
authors.lastname: Hernández
authors.forename: J
authors.initials: J
authors.lastname: Egido
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008055:Lipids / Q000737:chemistry; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes; D012995:Solubility
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D008798:Mevalonic Acid