DIFFERENTIAL-EFFECTS OF LOVASTATIN ON MITOGEN-INDUCED CALCIUM INFLUX IN HUMAN CULTURED VASCULAR SMOOTH-MUSCLE CELLS

1 In this study the effect of lovastatin, an inhibitor of cholesterol and isoprenoid synthesis, on the rises in intracellular calcium concen tration ([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 sustain ed phase of [Ca2+](i) elevation in response to PDGF-BB but the respons es to AII, LDL and FCS were unaffected. Further experiments showed tha t lovastatin pretreatment inhibited PDGF-BB induced Ca2+ influx but no t intracellular Ca2+ release. This inhibition could be overcome by co- incubation with mevalonic acid. 3 Pretreatment of cells with the heter otrimeric G protein inhibitor pertussis toxin for up to 24 h completel y abolished AII-induced [Ca2+](i) rises but the response to PDGF-BB wa s unaffected. 4 The tyrosine kinase inhibitor genistein largely abolis hed PDGF-BB-induced [Ca2+](i) elevation but had no significant effect on AII-induced responses. 5 Pre-incubation with lovastatin had no effe ct on the level of tyrosine phosphorylation of PDGF-beta receptors (as measured by Western blot) in response to the PDGF-BB ligand. 6 PDGF-B B elicits Ca2+ influx via a tyrosine kinase-dependent mechanism distin ct from the heterotrimeric G protein coupled pathway utilized by AII. Lovastatin most likely acts by inhibition of isoprenylation (via block ade of isoprenoid synthesis) of an intermediate molecule involved in P DGF-BB-induced Ca2+ influx.