Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis

Abstract

Objective-The ubiquitin-proteasome system is the principal degradation route of intracellular and oxidized proteins, thus regulating many cellular processes conceivably important for atherosclerosis. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in human carotid artery plaques in relation to oxidative stress and clinical manifestation. Key Words: atherosclerosis Ⅲ carotid plaque Ⅲ endarterectomy Ⅲ oxidative stress Ⅲ proteasome Ⅲ stroke Ⅲ ubiquitin T he ubiquitin-proteasome system (UPS) is responsible for the nonlysosomal degradation of the majority of intracellular proteins, 1,2 thus playing a crucial role in the regulation of many cellular processes. 3 The process of ubiquitination requires various enzymatic activities, involving specific proteins, ie, E1, E2, E3, which activate and transfer polyubiquitin chains to target proteins, leading eventually to the formation of a complex which is recognized and degraded by the 26S proteasome complex. 4 This complex is composed of a 20S core particle that embodies the catalytic activity and 2 19S regulatory particles. The targets of the UPS include key regulators of cell cycle and apoptosis and various transcription factors, whose intracellular levels are finely tuned in the maintenance of the optimum equilibrium for cell division, growth, differentiation, signal transduction, and response to stress. 3,5 Many of these processes are crucially involved in the onset, progression, and complication of atherosclerosis. In particular the UPS plays a key role in the activation of NF-B, 6 which has been associated with coronary 7 and carotid 8 plaque instability. Moreover, the UPS degrades many molecules and regulators of apoptosis and angiogenesis, 3 crucial mechanisms of plaque formation and rupture. 9,10 It is therefore conceivable that dysregulation of the UPS plays a role in atherosclerotic plaque progression and tendency to rupture. Indeed, increased expression of ubiquitin conjugates has been demonstrated in human coronary plaque responsible for lethal myocardial infarction as compared with noninfarct related coronary lesions. 11 See coverA high rate of protein ubiquitination is associated with increased oxidative stress 12 especially in neurological disorders [13][14][15] and UPS has been demonstrated to be the principal system responsible for the degradation of oxidized proteins. 16 However, high-level oxidative stress can also impair UPS by reducing proteasome activity. 15,17 This could lead to intracellular accumulation of ubiquitinated substrates caused by an increased production and by a reduced degradation. As shown in the development of cataract, 18 intracellular ubiquitinated damaged proteins may eventually accumulate, form aggre-

Morning Blood Pressure Surge as a Destabilizing Factor of Atherosclerotic Plaque

“…Because of the study design, we cannot exclude whether the ubiquitin-proteasome dysregulation also may influence the atherosclerosis process through other pathways, such as apoptosis. 22 However, the concomitant presence of higher levels of ubiquitin, proteasome 20S, and NF-B in cultured monocytes of MPϩ patients suggests that the ubiquitinproteasome pathway may have a proinflammatory effect in MPϩ lesions. Thus, we can speculate that increased ubiquitin-proteasome activity in plaque macrophage as a consequence of oxidative stress overexpression may enhance the synthesis of NF-B in the same cell, possibly representing a crucial step in the pathophysiology of MPϩ plaque instability.…”

Ubiquitin-Positive Foam Cells are Identified in the Aortic and Mitral Valves with Atherosclerotic Involvement

“…The studied valves contained a few cells that were positive for p53; this finding also suggests that autophagic cell death-lysosomal proteolysis might affect these aortic valves, especially valves with calcification 21) ; however, increased oxidative stress was responsible for the inhibition of UPS activity leading to the accumulation of Ub proteins within the plaques. In addition, the accumulation of Ub conjugates has been directly correlated to apoptosis 17) . The affected valves containing Ub cells indicate that ubiquitinated proteins accumulate in some foam cells as acute cellular injury through inhibition of the UPS pathway; however, the number of apoptotic cells was not correlated in the present study.…”

“…UPS cause proteolysis and cell cycle progression, including apoptosis [1][2][3] , and many diseases may be related to the function of UPS. The accumulation of ubiquitinated proteins in a cell is a histological hallmark of erosclerotic lesions [16][17][18][19] . Molecular analyses of the cell cycle and signal transduction in cardiac valvular diseases have revealed an association with UPS processes; however, studies on valvular disease and UPS remain scarce [20][21][22] , and there has been little histological examination of Ub cells in valvular diseases 23,24) .…”

Modulation of Proteasome Activity by Vitamin E in THP‐1 Monocytes

“…CD36 expression is often increased at the atherosclerotic lesion by triggers such as oxLDL via PKB and PPARg activation (21). Interestingly, oxLDL has also been shown to inhibit the proteasome (63) and increased levels of ubiquitinated proteins and decreased proteasome activity were detected in unstable atherosclerotic plaques (12,64). It remains to be tested whether a-tocopherol can restore cellular proteasome activity after inhibition by oxLDL.…”