ECM turnover is governed by a dynamic balance amongst multiple factors, including MMP and their cognate inhibitors, TIMPs. We observed AngII-induced increases in TIMP1 and TIMP2 protein expression of 4 fold and 1.7 fold after chronic AngII-treatment, values that were consistent with previous reports. Interestingly, we found that bortezomib co-treatment suppressed AngII-induced expression of TIMP1 and TIMP2. These data support previous work showing that TIMP expression was reduced by Selumetinib proteasome inhibitors in other cell types such as cardiac fibroblasts in culture or in hearts of spontaneously hypertensive rats. Given the increased TIMP expression in aortic tissue collected from AngII-infused rats, we predicted that reduced MMP activity might be a mechanism underlying the increased aortic collagen deposition observed in the hypertensive rats. Contrary to our prediction, we observed that MMP2 activity was increased in the aorta harvested from rats with AngII-induced hypertension. However, this finding is not without precedent. In rats, AngII-treatment increased aortic MMP2 activity. Similarly, AngII infusions increased carotid artery MMP2 gelatinase activity in mice. Indeed Watts reported increases in both MMP2 activity and TIMP2 protein level in DOCA salt hypertensive rats. Moreover, in hypertensive patients, plasma MMP2 activity and TIMP1 protein level showed concurrent increases. Thus, the precise interaction of TIMPs and MMP is complex. In any case, we observed that co-treatment with bortezomib largely abrogated the AngII-induced increase in MMP activity. These data provide support for the view that proteasome inhibition affects the changes in aortic MMP activity associated with hypertension. Our findings are consistent with work in carotid artery atherosclerosis that reported that increased proteasome activity correlated with increased MMP expression. Collectively, these data support the idea that the proteasome is critically involved in controlling the balance of TIMP1/TIMP2 expression and MMP2 activity which in turn modulates aortic extracellular matrix turnover in hypertension. The mechanisms by which proteasome inhibition mediates these effects remain to be determined. The ubiquitin proteasome system is a pleiotropic cellular mechanism that has influences on cell cycle regulation, apoptosis, transcription, protein turnover and cell signaling. Similarly, AngII is known to elicit its effects via multiple signaling pathways. Thus, there are numerous potential interactions between proteasome inhibition and AngII signaling that could account for the current observations. While beyond the scope of the present study, each of these possibilities represents viable avenues for future follow up. Attractive possibilities include oxidative, inflammatory and proliferative mechanisms. It is known that ROS play a role in mediating the vascular actions of AngII. Previous work by Stangl showed that the proteasome was involved in modulating ROS accumulation in vascular smooth muscle. This group reported that bortezomib treatment lowered superoxide levels in the aorta of Dahl salt sensitive hypertensive rats. In the present study we observed that AngIIinduced hypertension was associated with an increase in aortic ROS that was also abrogated by treatment with bortezomib. Previous work has suggested several possibilities for this effect. Proteasome inhibition has been shown to increase antioxidative capacity by upregulating antioxidant proteins such as SOD1 and catalase. Alternatively, proteasome inhibition may upregulate nitric oxide synthase expression and activity as well as nitric oxide production which may effectively scavenge ROS. Lastly, proteasome inhibition may transcriptionally suppress NADPH oxidase expression. Irrespective of the precise mechanism by which proteasome inhibition suppresses ROS, this effect may contribute to the antihypertensive effects of proteasome inhibition since ROS are a key signaling mechanism downstream of AngII. ROS are linked with inflammatory responses. Increasing evidence suggests that T cell mediated inflammatory mechanisms contribute to hypertension and hypertensive remodeling. In the present study we observed that AngII hypertension-induced increases in aortic VCAM-1 immunoreactivity were abolished by treatment with bortezomib. These data are consistent with those of Ludwig who showed previously that bortezomib treatment of Dahl salt sensitive hypertensive rats reduced both ROS and VCAM-1 expression in the aorta. Thus, proteasome inhibition appears to effectively inhibit hypertension associated aortic ROS and inflammation in a model independent manner. Whether this effect is mediated through actions on T cells remains an open question. However, at present, it is not clear if the ability of proteasome inhibition to reduce inflammation underlies the anti-hypertensive action of bortezomib. Ludwig did not observe a significant reduction in blood pressure despite a marked anti-inflammatory action of bortezomib.