| Background and objective: Atherosclerosis (AS), a current leading hazard to human health, is acommon, inflammatory, and chronic disease. The pathophysiology of this malady is nowprevalently thought to be an inflammatory process, however, its whole mechanism remainslargely obscure. Ubiquitin-proteasome system (UPS), an ATP-dependent, non-lysosomalpathway for degradation of intracellular proteins, plays a leading role in activation of the NF-κBpathway, which is involved in multi-inflammatory processes, however, its involvement in theprocesses of AS remains to be confirmed. On the other hand, inconsistent views, recently arises,on the impairment of the activity of proteasome 26S and 20S by oxidative stress, so thecorrelations between the oxidative stress and UPS have to be demonstrated. Non-steroidalanti-inflammatory drugs (NSAIDs) can, via the UPS, induce some cancer cells apoptosis andinhibit proliferation, however, its effects on AS, as an inhibitor of LIPS, remains to be studied,especially in the aspects of the impairment of the UPS, the activation of NF-κB pathway and thepathogenesis of AS. Up to now, reports on these aspects remain scarce, so we hypothesis that ifUPS is fuctionally active in the pathogenesis of AS, aspirin as an inhibition of UPS may reducethe expression of the inflammatory factors and attenuate the progress of AS.Purposes: Establish the AS rabbit model, evaluate the function of UPS in the pathogenesis of ASinduced by aspirin, determine the oxaditive stress and the activity of 26S and 20S, assess therelationship of vascular pathological alterations and UPS and the activation of NF-κB pathway inthe condition induced by aspirin, try to demonstrate the role of UPS in the pathogenesis of AS.Materials and methods: 3-month old, weight matched, New Zealand male rabbits wererandomly divided into four groups: normal diet (N) or normal diet with aspirin (NI) oratherogenic diet without (H) or with aspirin (HI) for 12 weeks. Proteasome activity,concentrations of plasma lipids and levels of peroxidation were determined.Ubiquitin/ubiquitin-conjugates (Ub), IκBα, phosphorylated IκBα(pIκBα) and p65 wereinvestigated by Western blotting or immunochemistry.Results: (1) The AS animal model was successfully established; (2) Concentrations of plasmalipids TC, TG and LDL were higher in H or HI vs. N or NI (P＜0.05), whereas, HDL was foundno significant differences between the groups (P＞0.05). (3) The levels of MDA was foundsignificantly increased in H or HI vs. N or NI(P＜0.05), while, SOD and CAT were significantlyhigher in N or NI vs. H or HI (P＜0.05), respectively. (4) The activity of 26S was found no significant differences among N, NI and HI, by contrast, 20S was notly more active in H thanany other group (P＜0.05).(5) HE results showed that the vascular wall was notly thicker andatheroma was apprent in H vs.HI (P＜0.05); (6)Immunochemistry showed that Ub/UPC and IκBα/pIκBαwere mainly localized in subendothelium and media vascular smooth muscle cells andmore positive in HI vs. H, and so was the case in NI vs. N, by contrast, p65 was more positive inH, respectively (P＜0.05). (7) Western blots revealed that Ub/UPC, IκBα, and pIκBαwereincreased in NI vs. N or HI vs H, respectivelty, whereas, p65 in H was higher than any othergroup (P＜0.05), no significant difference was noted among the rest groups (P＞0.05).Conclusions: UPS may be functionally active in the process of AS, the activity of 26S was littleaffected in oxidative stress, while 20S was actively increased. Aspirin can, via the LIPS, partlyinhibit the activity of 20S or 26S, attenuate the pathogenesis of atheroma formation, attenuate thedegradation of IκBαand pIκBα, and lower the expression of p65, indicating that aspirin mayhave therapeutic effects on AS, and the UPS may be one of the new targets for the prevention ortreatment of AS.
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