Abstract 231: Angiotensin-(1-9) Antagonises Cardiac Remodelling in a Mouse Model of Angiotensin Ii-induced Hypertension.
The identification of angiotensin converting enzyme-2 (ACE2), generating angiotensin-(1-7) [Ang-(1-7)] which signals via the Mas receptor to inhibit pathophysiological effects in cardiovascular disease has led to the definition of a counter-regulatory axis of the renin angiotensin system (RAS). Recently, we showed that another angiotensin peptide, Ang-(1-9), may also be part of this counter-regulatory axis as it prevents cardiomyocyte hypertrophy via the angiotensin type 2 receptor (AT2R). Furthermore, infusion of Ang-(1-9) via osmotic minipumps into stroke-prone spontaneously hypertensive rats reduced cardiac fibrosis via the AT2R. Here, we investigated Ang-(1-9) in an acute model of AngII-induced hypertension in C57BL/6J mice. Ang-(1-9), Ang-(1-9)+PD123,319 (AT2R antagonist), or water (control) were co-infused with AngII for 2 weeks via osmotic minipumps. Blood pressure was monitored via radiotelemetry. Significant increases in mean arterial pressure were observed in AngII infused mice compared to control (control 108.8±5.7 mmHg; AngII 125.1± 8.4 mmHg; p>0.05) however co-infusion of Ang-(1-9) or Ang-(1-9) and PD123,319 did not affect AngII-induced hypertension (AngII+ Ang-(1-9) 122.4±10.3 mmHg; AngII+Ang-(1-9)+PD123,319 118.3±mmHg; n=6 mice). When assessing cardiac hypertrophy by heart weight/tibia length ratio Ang-(1-9) reduced AngII-induced cardiac hypertrophy (ratio heart weight/tibia length: control 9.4 ± 1.2; AngII 11.9 ± 0.6; AngII+Ang-(1-9) 8.2 ± 0.7; p<0.01). Sections of heart were stained with wheat germ agglutinin and cardiomyocyte size measured supporting an anti-hypertrophic effect of Ang-(1-9) via the AT2R (control 25.7±3.8 μm; AngII 28.8±3.8 μm; AngII+Ang-(1-9) 24.6±4.8 μm; AngII+Ang-(1-9)+PD123,319 27.7±3.2μm; p<0.05). Furthermore, quantification of fibrosis following staining with picrosirius red also showed a significant reduction in animals co-infused with Ang-(1-9) and AngII compared to AngII-infusion (p<0.05). Further studies are ongoing to analyse cardiac effects of Ang-(1-9) at gene and protein level. These data support a direct biological role for Ang-(1-9) in cardiac remodeling and highlights Ang-(1-9) as a potential new therapeutic target in cardiovascular disease.
- © 2012 by American Heart Association, Inc.