Agonist-Independent Constitutive Activity of Angiotensin II Receptor Promotes Cardiac Remodeling in Mice

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Abstract

The angiotensin II (Ang II) type 1 (AT1) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT1 receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II–independent AT1 receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT1 receptor under the control of α-myosin heavy chain promoter in angiotensinogen-knockout background (AT1Tg-AgtKO mice). In AT1Tg-AgtKO hearts, redistributions of the Gαq11 subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT1 receptor is constitutively activated independent of Ang II. As a consequence, AT1Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT1Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT1 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 AT1 receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT1 receptor is upregulated in the heart.

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