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Acute phorbol ester treatment inhibits thapsigargin-induced cell death in porcine aortic smooth muscle cells.

Abstract：

:We have previously shown that, in porcine aortic smooth muscle cells, endoplasmic reticulum (ER) stressor thapsigargin simultaneously activate the mitochondrial caspase-dependent death cascade and an extracellular signal-regulated kinase (ERK)-dependent pathway, which inhibits the caspase-independent death pathway. Our aim in the present study was to examine the effect of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on these processes. We found that thapsigargin induced autophagy, which led to cell death. Treatment of cells with PMA for 5min, which activates protein kinase C (PKC), partially inhibited thapsigargin-induced cell death, whereas PMA treatment for 24h, which downregulates PKC, did not. This protection after short PMA treatment was not due to inhibition of the thapsigargin-induced cytosolic calcium concentration increase, mitochondrial permeability transition pore (PTP) opening, or caspase-3 activation, but coincided with increased ERK phosphorylation and decreased autophagosome formation and the decreased autophagosome formation was prevented by the ERK kinase inhibitor PD98059. Thus, under conditions of ER stress caused by thapsigargin-induced disturbance of calcium homeostasis, PKC activation induced ERK phosphorylation, which inhibited autophagic, but not apoptotic, cell death. After acute PMA treatment, protection against thapsigargin-induced cell death was enhanced by the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone or the PTP blocker cyclosporin A, but decreased by PD98059 or the PKC inhibitor Go6983. Taken together, these results suggest that PKC activation alleviates ER stress and that this is attributable to enhanced ERK phosphorylation, which inhibits autophagic, but not apoptotic, cell death.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Lin KC,Liu PS,Peng PY,Chueh SH

doi

10.1016/j.ejphar.2012.04.015

subject

Has Abstract

pub_date

2012-07-05 00:00:00

pages

8-15

issue

1-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(12)00349-4

journal_volume

686

pub_type

杂志文章

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Acute phorbol ester treatment inhibits thapsigargin-induced cell death in porcine aortic smooth muscle cells.