Fig. 6.

Illustration of the effects of boronate-type proteasome inhibitor treatment (PSI) in addition to normal (N) or high-cholesterol (HC) for 12 weeks in domestic pigs. Compared with N, a 60% increase in coronary artery chymotrypsin-like proteasome activity is notable in HC and a 70% decrease in N+PSI and HC+PSI (panel A). This level of proteasome inhibition causes oxidative stress on the level of the intima, measurable, for instance, by DHE fluorescence, indicating in situ superoxide anion production similar to the degree observed in HC (panel B). Concomitantly, there is a decrease in the vasorelaxation response to the endothelium-dependent agonist bradykinin although more pronounced in PSI pigs (panel C). Along with endothelial dysfunction, intimal thickening develops in N+PSI similar to HC (panel B). Yet, even with a similar level of endothelial dysfunction, intimal thickening is greatly aggravated in HC+PSI. These observations suggest that, while chronic proteasome inhibition can be harmful under otherwise normal conditions, the consequences are much worse when it entails blunting a compensatory increase in proteasome activity. Modified and reproduced with permission from the American Heart Association.¹⁸