Inhibition of intracellular Ca2+ mobilisation by low antiproliferative concentrations of thapsigargin in human vascular smooth-muscle cells

Sonia D. Birkett, Jamie Y. Jeremy, Susan M. Watts, Nilima Shukla, Gianni D. Angelini, Craig A. McArdle

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Low nanomolar concentrations of thapsigargin, a modulator of intracellular Ca2+ ([Ca2+](i)) pools, inhibit vascular smooth-muscle cell (VSMC) proliferation. Because the mechanisms underlying this effect have not been defined, the effect of antiproliferative concentrations of thapsigargin on [Ca2+](i) in fura-2-loaded VSMCs was studied by using dynamic video imaging of [Ca2+](i). After seeding on coverslips, human VSMCs were incubated for 1-48 h with thapsigargin before loading with fura-2 or during imaging. Mobilisation of [Ca2+](i) was stimulated with 1 μM ionomycin in Ca2+-free medium and the increase in [Ca2+](i) detected by using Ca2+ imaging techniques. Continuous exposure of cells to low concentrations of thapsigargin (which failed measurably to increase in [Ca2+](i)) reduced the ionomycin response in a time-and dose-dependent manner (100% inhibition at 10 nM thapsigargin after 1 h exposure). After exposure of cells to 10 nM thapsigargin for 1 h followed by washing and further incubation for ≤72 h, there was a time-dependent recovery of the ionomycin response. Because the concentrations of thapsigargin and exposure times are identical to those that inhibit replication in VSMCs, it is proposed that depletion of [Ca2+](i) pools mediates the inhibitory effect of thapsigargin on VSMC proliferation.

Original languageEnglish
Pages (from-to)204-211
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Volume33
Issue number2
DOIs
StatePublished - Feb 1999
Externally publishedYes

Keywords

  • Intracellular calcium pools
  • Thapsigargin
  • Vascular smooth-muscle cell

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