title: Agonist-independent constitutive activity of angiotensin II receptor promotes cardiac remodeling in mice.
abstract: The angiotensin II (Ang II) type 1 (AT(1)) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT(1) receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II-independent AT(1) receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT(1) receptor under the control of α-myosin heavy chain promoter in angiotensinogen-knockout background (AT(1)Tg-AgtKO mice). In AT(1)Tg-AgtKO hearts, redistributions of the Gα(q11) subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT(1) receptor is constitutively activated independent of Ang II. As a consequence, AT(1)Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT(1)Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT(1) receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT(1) receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT(1) receptor is upregulated in the heart.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yasuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kudo-Sakamoto
authors.forename: Chizuru
authors.initials: C
authors.lastname: Yabumoto
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yano
authors.forename: Rie
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ozasa
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D012313:RNA / Q000235:genetics*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*; D018754:Ventricular Dysfunction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: C544066:Agtr1a protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D012313:RNA; C081643:candesartan