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Low nanomolar thapsigargin inhibits the replication of vascular smooth muscle cells through reversible endoplasmic reticular stress.

Abstract：

:Thapsigargin (TG), an inhibitor of Ca(2+) ATPase pumps in the endoplasmic reticulum (ER), inhibits replication of human vascular smooth muscle cell (hVSMC) at low nM concentrations. TG blocks replication of other cell types through promotion of ER stress (ERS). In order to determine whether ERS may mediate the cytostatic effect of TG in hVSMCs, the effect of TG on ERS in hVSMCs was studied by assessing markers of ERS: Immunoglobulin Heavy Chain Binding Protein (BiP), growth inhibitory transcription factor, GADD153, phosphorlylated eukaryotic initiation factor 2α (p-eIF2α) and phosphorlylated protein kinase R (p-PKR). hVSMCs derived from saphenous veins were rendered quiescent with serum-free medium for 96 h incubated with 10 nM TG at 37 °C for 24 h, then washed free of TG and incubated with 10% foetal calf serum (FCS) for a further 24 h. At selected times, BiP, GADD153, p-eIF2α, p-PKR and cyclin D1 expression was assessed. TG promoted a marked increase in BiP and GADD153, but suppressed cyclin D1 mRNA and protein expression. Under serum-free conditions p-eIF2α and p-PKR expression was not enhanced by TG. 15-24 h After removal of TG all these factors returned to levels seen in control cells. These data demonstrate that the inhibitory effect of 10nM TG on hVSMC replication is mediated through induction of ERS and associated factors that cessate replication and is reversible. These observations have implications in the aetiology and treatment of diseases that include atherogenesis, vein graft failure and restenosis.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Shukla N,Wan S,Angelini GD,Jeremy JY

doi

10.1016/j.ejphar.2013.05.036

subject

Has Abstract

pub_date

2013-08-15 00:00:00

pages

210-7

issue

1-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(13)00453-6

journal_volume

714

pub_type

杂志文章

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