Collectively these data suggest that, bortezomib treatment attenuated many of the events downstream of AngII stimulation that are associated with TWS119 hypertension and hypertensive aortic remodeling. We used an induced model of hypertension, the AngII infusion model that exhibits a gradual increase in MAP that stabilizes at hypertensive levels in about 72 hours. At day 12 of AngII infusion we observed an increase in MAP of approximately 30 mmHg. This value compares favorably with previous work using a similar approach. We found that hypertension did not develop in AngII infused rats co-treated with the proteasome inhibitor, bortezomib. Previous work examining the effects of proteasome inhibitors on hypertension is limited. Takaoka used a DOCA salt model that exhibited an increase in systolic arterial BEZ235 pressure of approximately 50 mmHg. Similarly, treatment of spontaneously hypertensive rats with another proteasome inhibitor, MG132 also failed to reduce blood pressure. The precise reasons for these discrepant findings are not immediately clear but may involve methodological differences. The dose of bortezomib used in the present study, a dose in the clinical range, was substantially higher than the doses of proteasome inhibitors used in Dahl rats or spontaneously hypertensive rats. While we cannot rule out a potential toxic effect of bortezomib at the dose we used, consistent with previous work using 200 mg/kg, we did not observe any overt signs of toxicity, such as weight loss. Although peripheral neuropathy was reported at this dose, we did not observe any overt signs consistent with this possibility. Alternatively, the different outcomes may represent differences in the fundamental mechanisms involved in these different models of hypertension. In any case the evidence currently supports the possibility that proteasome inhibition has an antihypertensive effect, at least in some forms of hypertension. Interestingly, these findings were obtained with three different inhibitors suggesting a general effect of proteasome inhibition per se and not the specific effects of individual drugs. Since AngII-induced activation of chymotrypsin-like activity in skeletal muscle was previously reported, we used this as a marker of effectiveness of the bortezomib treatment. As expected we found that AngII infusion was associated with an increase in chymotrypsin-like activity. This effect was largely attenuated by concurrent treatment with bortezomib. We had predicted that the bortezomib treatment alone would reduce chymotrypsin-like activity. Unexpectedly, we observed that bortezomib treatment alone did not affect basal chymotrypsin-like activity. One potential explanation for this observation is found in the work of Meiners, who reported that chronic inhibition of proteasome function triggers a compensatory upregulation of proteasome subunit expression.