Pathophysiological role of proteasome-dependent proteolytic pathway in endothelin-1-related cardiovascular diseases.
A proteasome-dependent proteolytic pathway serves important functions in cell cycle control and transcriptional regulation; however, its pathophysiological role in cardiovascular diseases is still unclear. We have recently obtained evidence that proteasome inhibitors are capable of preventing the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension or hypertrophy and of ischemic acute renal failure (ARF). Beneficial effects of the proteasome inhibitors were accompanied by a decrease in endothelin-1 (ET-1) content in the aorta and kidney of DOCA-salt and ischemic ARF animals, respectively. In addition, there is evidence showing that the reduction of nuclear factor-kappaB (NF-kappaB) activation is involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression in the cultured vascular endothelial cells. These findings suggest that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ET-1-related cardiovascular diseases, probably through the activation of NF-kappaB, and also that the use of proteasome inhibitors may be a novel approach to the treatment of cardiovascular diseases.
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, Japan.
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Takaoka
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Ohkita
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Matsumura
D058186:Acute Kidney Injury / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control; D019332:Endothelin-1 / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000517:prevention & control; D006984:Hypertrophy / Q000517:prevention & control; D007511:Ischemia / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors
D019332:Endothelin-1; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex