Reactive oxygen species-mediated homologous downregulation of angiotensin II type 1 receptor mRNA by angiotensin II.
Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of angiotensin (Ang) II through Ang II type 1 receptor (AT(1)-R). However, the role of ROS in the regulation of AT(1)-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT(1)-R by Ang II. Ang II (10(-6) mol/L) decreased AT(1)-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells. Preincubation of vascular smooth muscle cells with N:-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT(1)-R mRNA. The effect of NAC was due to stabilization of the AT(1)-R mRNA that was destabilized by Ang II. The Ang II-induced AT(1)-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as by PD98059. Exogenous H(2)O(2) also suppressed AT(1)-R mRNA. These results suggest that the production of ROS and the activation of ERK are critical for the downregulation of AT(1)-R mRNA. The generation of ROS through stimulation of AT(1)-R not only mediates signaling of Ang II but also may play a crucial role in the adaptation process of AT(1)-R to the sustained stimulation of Ang II.
Ichiki
T
T
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. ichiki@cardiol.med.kyushu-u.ac.jp
Takeda
K
K
Tokunou
T
T
Funakoshi
Y
Y
Ito
K
K
Iino
N
N
Takeshita
A
A
D000111:Acetylcysteine / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001667:Binding, Competitive; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000975:Antioxidants; D005419:Flavonoids; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine