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195 Angiotensin-(1-9) Reduces Cardiac Dysfunction in a Model of Angiotensin II-Induced Hypertensive Heart Disease
  1. Katrin Nather1,
  2. Stuart A Nicklin1,
  3. Christopher M Loughrey1,
  4. Rhian M Touyz1,
  5. Mónica Flores-Muñoz2,
  6. Lauren Wills1
  1. 1University of Glasgow
  2. 2Universidad Veracruzana


Angiotensin II (AngII) is involved in the pathophysiology of cardiovascular diseases including hypertension, myocardial infarction and heart failure. The counter-regulatory axis of the renin angiotensin system is centred on angiotensin-converting-enzyme 2 generating angiotensin-(1-7) which opposes the pathological actions of AngII in the heart. We recently showed that angiotensin-(1-9) [Ang-(1-9)] is part of the counter-regulatory axis which acts on the angiotensin type 2 receptor to inhibit AngII-induced cardiomyocyte hypertrophy in vitro and the development of cardiac fibrosis and hypertrophy in the stroke prone spontaneously hypertensive rat.1 Here, we characterised chronic effects of AngII infusion on cardiac function in mice and assessed whether Ang-(1-9) can reverse AngII-induced cardiac pathology.

In study 1, C57BL/6J mice were infused with H2O (control), 24 μg/kg/hr or 48 μg/kg/hr AngII for 6 weeks via osmotic minipumps. A separate group was infused with Ang-(1-9) (48 μg/kg/hr) alone to assess direct effects on cardiac function. In study 2, mice were infused with H2O or 48 μg/kg/hr AngII for 2 weeks, minipumps were replaced and mice received either H2O, AngII or AngII with Ang-(1-9) for a further 2 weeks. Cardiac function was measured by echocardiography and histological staining for cardiac fibrosis and cardiomyocyte hypertrophy performed.

After 6 weeks AngII infusion, fractional shortening (FS) was significantly decreased with either dose [control 45.5 ± 1.8%; AngII (24 μg) 32.3 ± 1.8%; AngII (48μg) 36.6 ± 4.2%; p < 0.05]. However, 48 μg AngII accelerated the decline in cardiac function causing an acute reduction in FS by 2 weeks. Cardiac hypertrophy [heart weight/tibia length (HW/TL)] significantly increased with either AngII dose [control 10.0 ± 0.3; AngII (24 μg) 11.4 ± 0.4; AngII (48 μg) 12.2 ± 0.3; p < 0.05]. Furthermore, increased cardiomyocyte hypertrophy was observed [control 22.6 ± 0.3 μm; AngII (24 μg) 26.1 ± 0.9 μm; AngII (48 μg) 26.8 ± 1.0 μm; p < 0.05]. Cardiac fibrosis, assessed via collagen I and III immunohistochemistry, revealed AngII caused a significant increase in collagen I [control 3.2 ± 0.5%; AngII (24 μg) 5.6 ± 0.6%; AngII (48 μg) 5.03 ± 0.4%; p < 0.05] and III [control 2.0 ± 0.2%; AngII (24 μg) 3.6 ± 0.4%; AngII (48 μg) 4.8 ± 0.8%; p < 0.05]. Infusion of Ang-(1-9) alone had no effect on FS, HW/TL, cardiomyocyte hypertrophy or collagen I and III deposition. When Ang-(1-9) was infused with AngII after an initial 2 week AngII infusion, mice showed a recovery in cardiac function as measured by FS (control 50.5 ± 2.2%; AngII 33.6 ± 1.9%; AngII+Ang-(1-9) 42.7 ± 4.1%). Further studies are ongoing to assess the effects of Ang-(1-9) beyond 2 weeks.

These results demonstrate that Ang-(1-9) can limit AngII-induced cardiac dysfunction and therefore has therapeutic potential in a range of cardiovascular diseases.


  1. Flores-Munoz M et al. Hypertension. 2012;59(2):300-7

  • Angiotensin-(1-9)
  • Cardiac remodeling
  • Cardiac function

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