A proteasome inhibitor prevents vascular hypertrophy in deoxycorticosterone acetate-salt hypertensive rats.
1. In the present study, we investigated the potential of the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal (PSI) to prevent vascular hypertrophy induced by deoxycorticosterone acetate (DOCA) and salt in rats. 2. Vehicle (35% ethanol, 35% polyethylene glycol and 30% saline solution)-treated DOCA-salt rats developed marked hypertension at 4 weeks. Morphological studies on the rats given vehicle showed aortic hypertrophy, with a significant increase in wall thickness, wall area and wall-to-lumen ratio. A significant decrease in vascular wall hypertrophy was observed in PSI (3 mg/kg)-treated DOCA-salt rats. In addition, a marked increase in aortic endothelin (ET)-1 content was evident in vehicle-treated DOCA-salt rats compared with findings in sham-operated rats. A significant attenuation of this increase occurred in PSI-treated DOCA-salt rats. 3. These results indicate that PSI can prevent the vascular hypertrophy in DOCA-salt hypertensive rats and the effect is accompanied by suppression of ET-1 production in the aorta. We suggest that a proteasome-dependent proteolytic system has an important role in the development of vascular hypertrophy in cases of DOCA-salt-induced hypertension, possibly through the enhancement of ET-1 production in vascular tissues.
Takaoka
M
M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan. takaoka@oups.ac.jp
Ohkita
M
M
Itoh
M
M
Kobayashi
Y
Y
Okamoto
H
H
Matsumura
Y
Y
D000465:Algorithms; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000473:pathology*; D003546:Cysteine Endopeptidases; D003900:Desoxycorticosterone; D019332:Endothelin-1 / Q000096:biosynthesis; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011480:Protease Inhibitors; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D003900:Desoxycorticosterone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex