The proteasome-dependent proteolytic pathway serves important functions in cell cycle control and transcriptional regulation; however, its pathophysiological role in vivo is still unclear. We recently obtained evidence that a proteasome inhibitor is capable of preventing the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension and of ischemic acute renal failure (ARF). Beneficial effects of the proteasome inhibitor were accompanied by a decrease in endothelin-1 content in the aorta and kidney of DOCA-salt and ischemic ARF animals, respectively. These findings suggest that the use of proteasome inhibitors may be a novel approach to the treatment of cardiovascular diseases.