This aspect of the action of proteasome inhibition on vascular inflammation and its link to hypertension warrants further in depth study. Lastly, vascular hypertrophy may arise in part via increases in VSMC proliferation. AngII was shown to increase the number of proliferating VSMC in the aorta. Similarly, we observed that AngII hypertension was associated with an increase in aortic immunoreactive Ki67, a marker of proliferating cells. The AngII hypertension-associated increase in Ki67 was attenuated by concurrent treatment with bortezomib. Thus, interruption of AngII induced VSMC proliferation may be one mechanism by which bortezomib prevented the aortic hypertrophic remodeling observed in the present study. Alternatively, proteasome inhibition was reported to induce apoptosis in aortic vascular smooth muscle cells in culture. It is conceivable therefore that proteasome inhibitor-induced apoptosis counterbalanced the increase in proliferation observed in the AngII treated aorta to prevent the increase in wall to lumen ratio recorded in this treatment group. Since we did not measure apoptosis in the present study we cannot rule out this possibility. However, it should be noted that proteasome-induced aortic vascular smooth muscle apoptosis was noted at high concentrations. It has been proposed that the effect of proteasome inhibition on vascular smooth muscle cell apoptosis is concentration dependent, with lower concentrations actually inducing a protective effect. While we did not measure plasma concentrations of bortezomib in the present study, our observation that bortezomib treatment alone did not reduce wall to lumen ratio suggests that the dose of bortezomib used was not overtly toxic to vascular smooth muscle cells. Irrespective of the precise mechanism, the data obtained in the present work is consistent with the view that proteasome inhibition can, under certain conditions, reduce hypertensive hypertrophic remodeling of the aorta. Collectively, these data suggest that bortezomib, presumably via its ability to inhibit the proteasome, exerts an inhibitory effect on multiple AngII-mediated actions that result in hypertension and hypertension associated aortic remodeling. Thus, it is tempting to speculate that proteasomal activity is required to activate an early step in the AngII signaling cascade leading to hypertension and hypertension-induced aortic remodeling. Hypertensive vascular remodeling is an adaptive response of blood vessels to normalize wall stress. However, these structural MK-0683 149647-78-9 changes can contribute to exacerbation of both hypertension and its sequelae. Hypertension-induced collagen deposition can augment the stiffness of the aorta and other large arteries to increase pulse pressure. Both increased mean arterial pressure and pulse pressure are associated with increased end-organ damage and related cardiovascular diseases. Growing evidence implicates the vascular UPS system as an important mechanism controlling vascular physiology and pathophysiology. In the present work, concurrent treatment with bortezomib attenuated AngII-induced hypertension, cell proliferation in the aorta, aortic ROS generation and inflammation, and the associated pathological structural changes in the aorta. Thus, these experiments suggested that proteasome activity plays a critical role in this sequence of hypertension related processes. Interestingly bortezomib treatment was also reported to attenuate pulmonary artery remodeling in pulmonary hypertension. Bortezomib is a reversible proteasome inhibitor which is currently approved for treatment of cancer. Its use in this setting is associated with considerable adverse effects which likely preclude the use of bortezomib per se for the treatment of hypertension. However, further understanding of the mechanisms by which the proteasome is involved in hypertension and vascular structural remodeling may reveal novel targets that may be more selective for pharmacological treatment of hypertension, hypertensive remodeling or both. The HIV-1 protease enzyme has a homodimeric C-2 symmetric structure and each monomer contributes one catalytic aspartic residue and flexible flap, which is able to bind the substrates and inhibitors. In addition, a characteristic bound water molecule forms an hydrogen bonding network between the flaps and bond substrates creating a tetrahedral transition-state intermediate. These drugs target HIV-protease enzyme which is a proteolytic enzyme responsible for cleaving large polyprotein precursor into biologically active protein products. HIV polyprotein precursor is encoded by the gag and gag-pol genes.