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Croons V, Martinet W, Herman AG, De Meyer GR.
Differential effect of the protein synthesis inhibitors puromycin and
cycloheximide on vascular smooth muscle cell viability.
J Pharmacol Exp Ther. 2008 Jun;325(3):824-32.
Division of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610
Wilrijk, Belgium. valerie.croons@ua.ac.be
Recent evidence indicates that the protein synthesis inhibitor cycloheximide
triggers selective macrophage death in rabbit atheroma-like lesions without
affecting smooth muscle cells (SMCs) or the endothelium, thereby favoring a
stable plaque phenotype. In this study, we report that puromycin, a
protein synthesis inhibitor with a different mode of action but with similar
ability to inhibit de novo protein synthesis, did not reveal plaque-stabilizing
effects. The macrophage and the SMC content readily decreased in puromycin-treated
atheroma-like lesions in rabbit carotid arteries. Moreover, puromycin
induced apoptosis in macrophages and SMCs in vitro. Puromycin-treated
SMCs showed signs of endoplasmic reticulum (ER) stress, as demonstrated by CCAAT/enhancer-binding
protein homologous protein (CHOP) protein expression, splicing of X-box-binding
protein 1 mRNA, and phosphorylation of eukaryotic translation initiation factor
2alpha. The ER stress inducer thapsigargin up-regulated CHOP protein expression
in SMCs without affecting their viability, indicating that ER stress not
necessarily results in cell death. Puromycin, but not thapsigargin, activated
the ER stress-related caspase-12. Treatment of SMCs with a combination of
cycloheximide and puromycin inhibited ER stress and partially improved SMC
viability. In addition, puromycin, but not cycloheximide or thapsigargin,
induced intracellular accumulation of polyubiquitinated proteins in SMCs,
whereas the proteasome function was not affected. Taken together, puromycin,
in contrast to cycloheximide, induces SMC apoptosis, thereby favoring an
unstable plaque phenotype. SMC death upon puromycin treatment could only be
partially prevented by cycloheximide, which completely blocked ER stress.
However, other or additional mechanisms, such as increased polyubiquitination of
proteins, might be involved in puromycin-induced SMC death.
PMID: 18322149
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