Abstract 2955: Cardiac Overexpression of Angiotensin II Type 1 Receptor Induces Left Ventricular Remodeling Without the involvement of Angiotensin II
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 demon-strated 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-AtgKO). In spite of systemic deficiency of AngII, echocardiographic examinations at 9 weeks of age revealed severe systolic dysfunction and chamber dilatation in AT1Tg-AtgKO mice, than in angiotensinogen-knockout (AtgKO) mice. Histologically, interstitial fibrosis was pronounced in AT1Tg-AtgKO hearts, and real-time RT-PCR analysis indicated that mRNA expressions of several fetal genes (Nppa, Nppb, Acta1) and collagen genes were significantly increased in AT1Tg-AtgKO hearts, compared with AtgKO hearts. In addition, the redistribution of Gαq11 subunits into the cytosol was significantly increased in AT1Tg-AtgKO hearts, compared with AtgKO hearts, suggesting that AT1 receptor is activated independently of AngII in AT1Tg-Atg KO hearts. 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. Therefore, the enhancement of the constitutive activity of AT1 receptor induced by upregulation of receptor expression may contribute to the pathogenesis of cardiovascular diseases.