Abstract 11085: Agonist-Independent Activation of the Angiotensin II Type 1 Receptor Contributes to Left Ventricular Remodeling in vivo
The angiotensin II (AngII) type 1 (AT1) receptor plays a crucial role in regulating the pathophysiological processes in the cardiovascular system. Recent in vitro studies demonstrated that AT1 receptor inherently shows spontaneous activity even in the absence of AngII. However, it remains unclear whether AngII-independent AT1 receptor activation is implicated in the pathogenesis of cardiovascular remodeling. Therefore, to elucidate the role of AngII-independent AT1 receptor activation in in vivo hearts, we generated transgenic mice overexpressing AT1 receptor under the control of the α-myosin heavy chain promoter in the Angiotensinogen-knockout background (AT1Tg-AgtKO). In spite of systemic deficiency of AngII, the redistribution of Gαq11 subunits into the cytosol was significantly increased in AT1Tg-AgtKO hearts, compared with Angiotensinogen-knockout (AgtKO) hearts. Furthermore, AT1Tg-AgtKO hearts showed a significant increas in the phosphorylation levels of extracellular signal-regulated kinases (ERKs) compared with AgtKO hearts, suggesting that AT1 receptor is activated independently of AngII in AT1Tg-AgtKO hearts. As a consequence, AT1Tg-AgtKO mice showed severe systolic dysfunction and chamber dilatation, compared with AgtKO mice, as revealed by echocardiographic examination. Histologically, interstitial fibrosis was pronounced in AT1Tg-AgtKO hearts, and real-time RT-PCR analysis indicated that mRNA expressions of several fetal genes and collagen genes were significantly increased in AT1Tg-AgtKO hearts, compared with AgtKO hearts. Cardiac remodeling in AT1Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for AT1 receptor, but not by its derivative candesartan-7H, which is deficient of inverse agonism due to a lack of the carboxyl group of candesartan. In conclusion, constitutive activity of AT1 receptor under basal conditions contributes to the left ventricular remodeling even in the absence of AngII, when AT1 receptor is overexpressed in the heart. In this sense, inverse agonist activity emerges as an important pharmacological parameter for AT1 receptor blockers that will improve therapeutic efficacy in the treatment of cardiovascular remodeling.
- © 2010 by American Heart Association, Inc.