Abstract 231: An Angiotensin II Type I Receptor Mutant Ameliorates The Hypertension And Cardiac Hypertrophy Caused By Chronic Angiotensin II Infusion In Transgenic Mice
Angiotensin II (AngII) type 1 (AT1) receptor regulates cardiovascular function by activating various signal pathways. We have shown previously the signaling profiles of various mutant AT1 receptors expressed in HEK-293 cells. Using these results, we generated transgenic mice in which the third intracellular loop and C-terminus of the AT1 receptor have been engineered [AB3T] so that a number of signals have been altered. Work on aortic endothelial cells isolated from the transgenic mice illustrated an altered signaling pattern in response to AngII which includes the de novo inactivation of Akt, RhoA and NFkB, reduction in the expression of endothelin-1 and a sizable increase in activated eNOS as compared to cells from wild type (WT) mice. In contrast, the phosphatidylinositol turnover (Galphaq coupling), arachidonic acid release (Galphai coupling), calcium influx and ERK activation did not change. In vivo the AB3T transgenic mice (n = 15) showed similar basal phenotype as WT mice (n= 15), but displayed a delayed onset of hypertension, where pressures were significantly lower (p < 0.05) as measured on day 3, 4, 7 and 14 in response to continuous AngII infusion, with a difference of 20 mmHg by day 14 of infusion. There was also a significantly larger heart to total body weight ratio (p = 0.036) in the WT mice where the heart weight is 0.441 ± 0.008 % of total body weight compared to the transgenic mice at 0.416 ± 0.008 %. In conclusion, overexpression of the AB3T mutant receptor in mice diminished Akt and RhoA activation and lessened the hypertension and cardiac hypertrophy caused by chronic AngII infusion. The transgenic model suggests that AT1 mediated Akt and RhoA signaling plays an important role in regulating blood pressure and cardiac hypertrophy in vivo.