Angiotensin-(1-9) antagonises Angiotensin II-induced cardiac remodeling via the angiotensin type 2 receptor

Flores, M., Graham, D. , Dominiczak, A.F. , Milligan, G. , Baker, A.H. and Nicklin, S.A. (2012) Angiotensin-(1-9) antagonises Angiotensin II-induced cardiac remodeling via the angiotensin type 2 receptor. Proceedings of the Physiological Society, 27, C1.

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The renin-angiotensin system (RAS) regulates cardiovascular physiology mainly via angiotensin II (AngII) engaging the angiotensin type 1 or type 2 receptors (AT1R and AT2R). Classical AngII actions are AT1R-mediated, while the AT2R may counteract AT1R signalling. However recent identification of the ACE2/Ang-(1-7)/Mas has led to the definition of a counter-regulatory axis of the RAS. Novel peptides of the counter-regulatory axis of the RAS, angiotensin 1-7 [Ang-(1-7)] and angiotensin 1-9 [Ang-(1-9)], have been identified as potential therapeutic molecules. Ang-(1-7) has been shown to antagonise the pathological actions of AngII through the receptor Mas. Recently, we showed that Ang-(1-9) has an anti-hypertrophic effect on AngII-induced rat neonatal cardiomyocytes, signalling through the angiotensin type 2 receptor (AT2R)1. Furthermore, infusion of Ang-(1-9) via osmotic minipumps to the stroke-prone spontaneously hypertensive rat reduced cardiac fibrosis via the AT2R)2. To further investigate the actions of Ang-(1-9) in an acute model of hypertension we infused AngII (24µg/kg/hr) in mice to induce hypertension. Ang-(1-9) (48µg/kg/hr), Ang-(1-9)+PD123,319 (AT2R blocker) (20mg/kg/day), or water (control) were co-infused with AngII for 2 weeks via osmotic minipumps. Blood pressure was monitored via radiotelemetry (for radiotelemetry probe and osmotic minipump implantation mice were anesthetized with 1.5% isofluorane in 1 L/min O2 for the duration of the surgical implantation procedure). Significant increases in mean arterial pressure (MAP) were observed in AngII infused mice compared to control (control 108.8 ± 5.7 mmHg; AngII 125.1 ± 8.4 mmHg; p><0.05; n= 6 mice; two way ANOVA) 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 ± 6.8mmHg; n=6 mice; two way ANOVA). However, Ang-(1-9) co-infusion was able to reduce AngII-induced cardiac hypertrophy (ratio heart weight/tibia length: Control 9.43 ± 1.2 mg; AngII 11.69 ± 0.6 mg; Ang-(1-9) 8.22 ± 0.7 mg; p<0.01; n=6 mice; one way ANOVA). Staining of cardiac sections with wheat germ agglutinin and measurement of cardiomyocyte size confirmed these results (Control 25.73 ± 3.8 µm; AngII 28.78 ± 3.8 µm; Ang-(1-9) 24.6 ± 4.8 µm; p<0.05; one way ANOVA). Cardiac fibrosis was assessed by picrosirius red staining and quantified by image analysis software. Mice co-infused with Ang-(1-9) showed a reduction in cardiac fibrosis when compared to AngII-infused animals (control 0.12 ± 0.16%; AngII 1.28 ± 2.2%; Ang-(1-9) 0.52 ± 0.75%; p<0.05; one way ANOVA). The effects of Ang-(1-9) were reversed by PD123,319 co-infusion. In summary Ang-(1-9) was able to reduce cardiac hypertrophy and fibrosis in an acute animal model of hypertension without effecting blood pressure. 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Baker, Professor Andrew and Graham, Dr Delyth and Flores, Dr Monica and Nicklin, Professor Stuart and Milligan, Professor Graeme and Dominiczak, Professor Anna
Authors: Flores, M., Graham, D., Dominiczak, A.F., Milligan, G., Baker, A.H., and Nicklin, S.A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Proceedings of the Physiological Society
Publisher:The Physiological Society

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
519461Dissecting the mechanism of action of the novel renin angiotensin hormone angiotensin1-9Stuart NicklinMedical Research Council (MRC)G0901161RI CARDIOVASCULAR & MEDICAL SCIENCES