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Proteasome inhibitor bortezomib promotes a rupture-prone plaque phenotype in ApoE-deficient mice

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Abstract

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.

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Acknowledgments

The authors are indebted to Rita Van den Bossche and Hermine Fret for their excellent technical assistance. This work was financially supported by the Fund for Scientific Research (FWO)-Flanders (projects G.0112.08 and G.0113.06), the Bekales Foundation and the University of Antwerp (NOI-BOF). Jozef Van Herck is a research assistant of the FWO-Flanders. Wim Martinet is a postdoctoral fellow of the FWO-Flanders.

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Authors and Affiliations

  1. Division of Cardiology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium

    Jozef Leo Van Herck & Christiaan J. Vrints

  2. Division of Pharmacology, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Guido R. Y. De Meyer, Wim Martinet, Hidde Bult & Arnold G. Herman

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  1. Jozef Leo Van Herck
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  2. Guido R. Y. De Meyer
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Correspondence to Jozef Leo Van Herck.

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Van Herck, J.L., De Meyer, G.R.Y., Martinet, W. et al. Proteasome inhibitor bortezomib promotes a rupture-prone plaque phenotype in ApoE-deficient mice. Basic Res Cardiol 105, 39–50 (2010). https://doi.org/10.1007/s00395-009-0054-y

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