Angiotensin1-9 antagonises pro-hypertrophic signalling in cardiomyocytes via the angiotensin type 2 receptor

Flores-Munoz, M., Smith, N. J., Haggerty, C., Milligan, G. and Nicklin, S. A. (2011) Angiotensin1-9 antagonises pro-hypertrophic signalling in cardiomyocytes via the angiotensin type 2 receptor. Journal of Physiology, 589(4), pp. 939-951. (doi: 10.1113/jphysiol.2010.203075)

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The renin-angiotensin system (RAS) regulates blood pressure mainly via the actions of angiotensin (Ang)II, generated via angiotensin converting enzyme (ACE). The ACE homologue ACE2 metabolises AngII to Ang1-7, decreasing AngII and increasing Ang1-7, which counteracts AngII activity via the Mas receptor. However, ACE2 also converts AngI to Ang1-9, a poorly characterised peptide which can be further converted to Ang1-7 via ACE. Ang1-9 stimulates bradykinin release in endothelium and has antihypertrophic actions in the heart, attributed to its being a competitive inhibitor of ACE, leading to decreased AngII, rather than increased Ang1-7. To date no direct receptor-mediated effects of Ang1-9 have been described. To further understand the role of Ang1-9 in RAS function we assessed its action in cardiomyocyte hypertrophy in rat neonatal H9c2 and primary adult rabbit left ventricular cardiomyocytes, compared to Ang1-7. Cardiomyocyte hypertrophy was stimulated with AngII or vasopressin, significantly increasing cell size by approximately 1.2-fold (P < 0.05) as well as stimulating expression of the hypertrophy gene markers atrial natriuretic peptide, brain natriuretic peptide, beta-myosin heavy chain and myosin light chain (2- to 5-fold, P < 0.05). Both Ang1-9 and Ang1-7 were able to block hypertrophy induced by either agonist (control, 186.4 mu m; AngII, 232.8 mu m; AngII+Ang1-7, 198.3 mu m; AngII+Ang1-9, 195.9 mu m; P < 0.05). The effects of Ang1-9 were not inhibited by captopril, supporting previous evidence that Ang1-9 acts independently of Ang1-7. Next, we investigated receptor signalling via angiotensin type 1 and type 2 receptors (AT(1)R, AT(2)R) and Mas. The AT(1)R antagonist losartan blocked AngII-induced, but not vasopressin-induced, hypertrophy. Losartan did not block the antihypertrophic effects of Ang1-9, or Ang1-7 on vasopressin-stimulated cardiomyocytes. The Mas antagonist A779 efficiently blocked the antihypertrophic effects of Ang1-7, without affecting Ang1-9. Furthermore, Ang1-7 activity was also inhibited in the presence of the bradykinin type 2 receptor antagonist HOE140, without affecting Ang1-9. Moreover, we observed that the AT(2)R antagonist PD123,319 abolished the antihypertrophic effects of Ang1-9, without affecting Ang1-7, suggesting Ang1-9 signals via the AT(2)R. Radioligand binding assays demonstrated that Ang1-9 was able to bind the AT(2)R (pK(i) = 6.28 +/- 0.1). In summary, we ascribe a direct biological role for Ang1-9 acting via the AT(2)R. This has implications for RAS function and identifying new therapeutic targets in cardiovascular disease.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Milligan, Professor Graeme and Smith, Dr Nicola
Authors: Flores-Munoz, M., Smith, N. J., Haggerty, C., Milligan, G., 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 > School of Life Sciences
Journal Name:Journal of Physiology
Publisher:Wiley-Blackwell Publishing
ISSN (Online):1469-7793
Published Online:20 December 2010
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