Significance: Atherosclerosis is a vascular disease of worldwide significance with fatal complications such as myocardial infarction, stroke, and peripheral artery disease. Atherosclerosis is recognized as a chronic inflammatory disease leading to arterial plaque formation and vessel narrowing in different vascular beds. Besides the strong inflammatory nature of atherosclerosis, it is also characterized by proliferation, apoptosis, and enhanced oxidative stress. The ubiquitin-proteasome system (UPS) is the major intracellular degradation system in eukaryotic cells. Besides its essential role in the degradation of dysfunctional and oxidatively damaged proteins, it is involved in many processes that influence disease progression in atherosclerosis. Hence, it is logical to ask whether targeting the proteasome is a reasonable and feasible option for the treatment of atherosclerosis. Recent Advances: Several lines of evidence suggest stage-specific dysfunction of the UPS in atherogenesis. Regulation of key processes by the proteasome in atherosclerosis, as well as the modulation of these processes by proteasome inhibitors in vascular cells, is outlined in this review. The treatment of atherosclerotic animal models with proteasome inhibitors yielded partly opposing results, the potentially underlying reasons of which are discussed here. Critical Issues and Future Directions: Targeting UPS function in atherosclerosis is a promising but challenging option. Limitations of current proteasome inhibitors, dose dependency, and the cell specificity of effects, as well as the potential of future therapeutics are discussed. A stage-specific in-depth exploration of UPS function in atherosclerosis in the future will help identify targets and windows for beneficial intervention. Antioxid. Redox Signal. 21, 2344–2363.
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