Journal
HYPERTENSION
Volume 59, Issue 3, Pages 627-U251Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.111.175208
Keywords
ARB; cardiac dysfunction; fibrosis; G protein-coupled receptor; inverse agonist
Categories
Funding
- Japan Society for the Promotion of Science [KAKENHI 20390218, 21229010, 23390213]
- Health and Labor Sciences Research grants
- Kowa Life Science Foundation
- Takeda Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Uehara Memorial Foundation
- Ichiro Kanehara Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Suzuken Memorial Foundation
- Grants-in-Aid for Scientific Research [21229010, 23689038, 23126504, 23659417, 23390213, 21390237] Funding Source: KAKEN
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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 alpha-myosin heavy chain promoter in angiotensinogen-knockout background (AT(1)Tg-AgtKO mice). In AT(1)Tg-AgtKO hearts, redistributions of the G alpha(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. (Hypertension. 2012; 59: 627-633.). Online Data Supplement
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