Angiotensin II type 2 receptor gene transfer downregulates angiotensin II type 1a receptor in vascular smooth muscle cells.
Two distinct subtypes of angiotensin (Ang) II receptors, type 1 (AT(1)) and type 2 (AT(2)), have been identified. Vascular smooth muscle cells (VSMCs) usually express AT(1) receptor. To elucidate the direct effects of the AT(2) receptor on the AT(1) receptor in VSMCs, we transfected AT(2) receptor gene into cultured rat VSMCs. Overexpression of AT(2) receptor significantly decreased expression of AT(1a) receptor at both the mRNA and protein levels in the presence and absence of Ang II in VSMCs. Overexpression of AT(2) receptor increased expression of bradykinin and inducible NO in the presence and absence of Ang II in VSMCs. Bradykinin B(2) receptor antagonist HOE-140 and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) inhibited the decreases in AT(1a) receptor expression by the overexpression of AT(2) receptor in VSMCs. L-Arginine augmented the decrease in AT(1a) receptor expression. Overexpression of AT(2) receptor suppressed basal DNA synthesis and proliferation of VSMCs and abolished response of DNA synthesis to Ang II in VSMCs. Our results demonstrate that overexpression of the AT(2) receptor downregulates AT(1a) receptor expression in rat VSMCs in a ligand-independent manner that is mediated by the bradykinin/NO pathway. Downregulation of AT(1a) receptor is a novel mechanism by which the AT(2) receptor regulates growth and metabolism of VSMCs.
Jin
Xue-Qing
XQ
Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Fukuda
Noboru
N
Su
Jin-Zi
JZ
Lai
Yi-Mu
YM
Suzuki
Ryo
R
Tahira
Yoshiko
Y
Takagi
Hiroto
H
Ikeda
Yukihiro
Y
Kanmatsuse
Katsuo
K
Miyazaki
Hitoshi
H
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014162:Transfection
D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C065679:icatibant; D004247:DNA; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester