NDLI: Differential effect of the protein synthesis inhibitors puromycin and cycloheximide on vascular smooth muscle cell viability.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Croons, Valerie Martinet, Wim Herman, Arnold G. De Meyer, Guido R. Y.
Description	Country affiliation: Belgium Author Affiliation: Croons V ( Division of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. valerie.croons@ua.ac.be)
Abstract	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.
File Format	HTM / HTML
ISSN	00223565
Issue Number	3
Volume Number	325
e-ISSN	15210103
Journal	Journal of Pharmacology and Experimental Therapeutics
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2008-06-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Research Support, Non-u.s. Gov't Dna-binding Proteins Comparative Study Carotid Arteries Cytology Male Macrophages Discipline Pharmacology Journal Article Puromycin Muscle, Smooth, Vascular Dietary Fats Atherosclerosis Caspase 12 Genetics Protein Synthesis Inhibitors Cell Line Rabbits Cell Survival Rna, Messenger Pharmacology Administration & Dosage Metabolism Drug Effects Dna Fragmentation Myoblasts Nuclear Proteins Pathology Cycloheximide Myocytes, Smooth Muscle Animals Hypercholesterolemia Discipline Therapeutics Mice Transcription Factors In Vitro Techniques Apoptosis
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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