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  • Title: Differential effects of lovastatin on mitogen induced calcium influx in human cultured vascular smooth muscle cells.
    Author: Clunn GF, Lymn JS, Schachter M, Hughes AD.
    Journal: Br J Pharmacol; 1997 Aug; 121(8):1789-95. PubMed ID: 9283719.
    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.
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