© 1997 American Heart Association, Inc.
Articles |
Intracellular Calcium Mobilization Suppresses the TNF-
–Stimulated Synthesis of PAI-1 in Human Endothelial Cells
Indications That Calcium Acts at a Translational Level
From INSERM CJF 93-12, Laboratoire d'Hématologie, Faculté de Médecine, Marseille, France.
Correspondence to Gilles Nalbone, INSERM CJF 93-12, Laboratoire d'Hématologie, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille, Cedex 05, France.
Abstract We investigated in human umbilical vein
endothelial cells (HUVECs) the interaction between the
signaling pathways triggered by calcium mobilization and those affected
by human recombinant tumor necrosis factor- (TNF) on the expression
of type-1 plasminogen activator
inhibitor (PAI-1). Calcium ionophore A23187 alone exerted a
modest increase (50%) on PAI-1 synthesis. TNF alone increased PAI-1
accumulation in the culture medium in a time- and dose-dependent
fashion, but this increase was abolished when A23187 was added
simultaneously with TNF. The downregulating effect of
A23187 was not the result of impaired protein secretion, proteolysis,
cytotoxicity, or an apoptotic process. A23187 did not decrease
the TNF-enhanced PAI-1 mRNA level but did provoke a significant shift
in the distribution pattern of PAI-1 transcripts by increasing the
2.3-kb relative to the 3.2-kb form. Comparable inhibitory
effects on PAI-1 protein synthesis were observed when A23187 was added
7 hours after the onset of TNF stimulation, strongly suggesting a
posttranscriptional inhibitory action of calcium signaling
on TNF-stimulated PAI-1 synthesis. However, treatment with actinomycin
D showed that PAI-1 mRNA stability was not altered by the various
treatments. Chelation of extracellular calcium by EGTA did not prevent
the A23187-induced inhibition of TNF-stimulated PAI-1 protein
synthesis, emphasizing the role of internal calcium stores in the
inhibition of PAI-1 synthesis. Sucrose gradient fractionation of cell
lysates revealed that regardless of which treatment was used, both
PAI-1 mRNA transcripts exhibited similar sedimentation profiles in the
actively translating polysomal pool, suggesting that the A23187-induced
shift had no functional consequence on translation. However, in
TNF-stimulated cells, A23187 induced a higher proportion of PAI-1 mRNAs
that sedimented in fractions corresponding to less dense polysomes, a
phenomenon that usually reflects a slower initiation rate during mRNA
translation. A23187 also abolished the increase in PAI-1 synthesis
induced by recombinant human interleukin 1ß, and thapsigargin exerted
effects comparable to those of A23187 on PAI-1 synthesis in
TNF-stimulated cells. It is proposed that in HUVECs, the A23187-induced
release of calcium from endoplasmic stores suppresses at the
translational level the increase in PAI-1 synthesis triggered by
proinflammatory cytokines.
Key Words: endothelium • PAI-1 • cytokines • calcium • translation
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