Changes in Systolic and Diastolic Function in a Mouse Model Overexpressing Cardiac Angiotensin II AT-1 Receptor

pp. 473-479

Abstract

Angiotensin II (Ang II) is involved in various pathophysiological processes through the activation of Ang II AT-1 receptors. The purpose of this study was to assess
in vivo and in vitro systolic and diastolic ventricular function in mice overexpressing the cardiac-specific AT-1 receptor (AT1R). A second objective was to determine whether acute and chronic ATIR blockade revert the changes in ventricular function.
Mice were divided into four experimental groups. The first group included non-transgenic animals (NTG, n=10), the second group consisted of transgenic mice (TG, n=7) with cardiac-specific AT1R overexpression and the third and fourth groups were TG animals treated with losartan (L) for 7 (TG L7, n=9) and 30 days (TG L30, n=7), respectively. Transgenic animals exhibited left ventricular hypertrophy (LVH) which was only regressed with losartan treatment for 30 days. They also presented a significant decrease in shortening fraction from 47.1 ± 2.3% to 32.3 ± 1.3% (p <0.05) and in +dP/dtmax from 7073 ± 674 to 3897.5 ± 209.7 mm Hg/sec (p <0.05). Systolic dysfunction recovered with losartan treatment for 7 and 30 days. 
Isovolumic relaxation time and t1/2 were 24.1 ± 1.3 and 5.1 ± 0.5 ms, respectively, in the NTG group. These indexes increased to 33.1 ± 2.2 and 8.4 ± 0.4 ms, respectively, in TG mice (p <0.05). Diastolic dysfunction was completely reversed by losartan treatment for 7 and 30 days. The analysis of in vitro ventricular function with controlled variables confirmed in vivo findings.
In conclusion, cardiac-specific AT1R overexpression induces systolic and diastolic ventricular dysfunctionwhich is completely reversed by AT1R blockade. This beneficial effect is independent of left ventricular mass changes.