title: Differential effects of lovastatin on mitogen induced calcium influx in human cultured vascular smooth muscle cells.
abstract: 1. In this study the effect of lovastatin, an inhibitor of cholesterol and isoprenoid synthesis, on the rises in intracellular calcium concentration ([Ca2+]i) induced by platelet derived growth factor BB (PDGF-BB), angiotensin II (AII), low density lipoproteins (LDL) and foetal calf serum (FCS) was examined in human cultured vascular smooth muscle cells (VSMC) from saphenous vein. Changes in [Ca2+]i were measured in cell suspensions by the Ca2+ sensitive probe, fura 2. 2. Incubation with lovastatin for 24-26 h markedly reduced the peak rise and sustained phase of [Ca2+]i elevation in response to PDGF-BB but the responses to AII, LDL and FCS were unaffected. Further experiments showed that lovastatin pretreatment inhibited PDGF-BB induced Ca2+ influx but not intracellular Ca2+ release. This inhibition could be overcome by co-incubation with mevalonic acid. 3. Pretreatment of cells with the heterotrimeric G protein inhibitor pertussis toxin for up to 24 h completely abolished AII-induced [Ca2+]i rises but the response to PDGF-BB was unaffected. 4. The tyrosine kinase inhibitor genistein largely abolished PDGF-BB-induced [Ca2+]i elevation but had no significant effect on AII-induced responses. 5. Pre-incubation with lovastatin had no effect on the level of tyrosine phosphorylation of PDGF-beta receptors (as measured by Western blot) in response to the PDGF-BB ligand. 6. PDGF-BB elicits Ca2+ influx via a tyrosine kinase-dependent mechanism distinct from the heterotrimeric G protein coupled pathway utilized by AII. Lovastatin most likely acts by inhibition of isoprenylation (via blockade of isoprenoid synthesis) of an intermediate molecule involved in PDGF-BB-induced Ca2+ influx.
authors.affiliation: Department of Clinical Pharmacology, Imperial College of School of Medicine at St Mary's, London.
authors.forename: G F
authors.initials: GF
authors.lastname: Clunn
authors.forename: J S
authors.initials: JS
authors.lastname: Lymn
authors.forename: M
authors.initials: M
authors.lastname: Schachter
authors.forename: A D
authors.initials: AD
authors.lastname: Hughes
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis
chemical_list: D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D008148:Lovastatin; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D002118:Calcium