Proteasome inhibitor bortezomib promotes a rupture-prone plaque phenotype in ApoE-deficient mice.
The ubiquitin-proteasome system is involved in the development and progression of atherosclerosis. The aim of this study was to investigate whether plaque composition is affected by proteasome function. In vitro, the potent and selective proteasome inhibitor bortezomib induced apoptosis in both cultured smooth muscle cells (SMCs) and activated macrophages. This effect was associated with increased expression of C/EBP homologous protein and cleavage of caspase-12, indicative of endoplasmic reticulum stress. The sensitivity to the proapoptotic effects of proteasome inhibition correlated with the protein synthesis rate. Proteasome inhibition in explanted atherosclerotic plaques of ApoE-deficient mice resulted in a significant decrease in SMCs and macrophages, indicating that both cell types in the atherosclerotic plaque were susceptible to the proapoptotic effects of proteasome inhibition. In vivo proteasome inhibition in ApoE-deficient mice did not affect plaque size or composition of early atherosclerotic plaques, but resulted in a significant decrease in collagen content as well as a significant enlargement of the necrotic core in advanced atherosclerotic plaques. In conclusion, our results indicate that an impaired proteasome function promotes features of a more rupture-prone plaque phenotype.
Van Herck
Jozef Leo
JL
Division of Cardiology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. jozef.vanherck@ua.ac.be
De Meyer
Guido R Y
GR
Martinet
Wim
W
Bult
Hidde
H
Vrints
Christiaan J
CJ
Herman
Arnold G
AG
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D005260:Female; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D011817:Rabbits; D012422:Rupture, Spontaneous
D001057:Apolipoproteins E; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex