Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor

Monica Flores-Munoz, Lorraine M Work, Kirsten Douglas, Laura Denby, Anna F Dominiczak, Delyth Graham, Stuart A Nicklin

Research output: Contribution to journalArticlepeer-review

Abstract

The renin-angiotensin system regulates cardiovascular physiology via angiotensin II engaging the angiotensin type 1 or type 2 receptors. Classic actions are type 1 receptor mediated, whereas the type 2 receptor may counteract type 1 receptor activity. Angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7) and angiotensin I to angiotensin-(1-9). Angiotensin-(1-7) antagonizes angiotensin II actions via the receptor Mas. Angiotensin-(1-9) was shown recently to block cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Here, we investigated in vivo effects of angiotensin-(1-9) via the angiotensin type 2 receptor. Angiotensin-(1-9) (100 ng/kg per minute) with or without the angiotensin type 2 receptor antagonist PD123 319 (100 ng/kg per minute) or PD123 319 alone was infused via osmotic minipump for 4 weeks into stroke-prone spontaneously hypertensive rats. We measured blood pressure by radiotelemetry and cardiac structure and function by echocardiography. Angiotensin-(1-9) did not affect blood pressure or left ventricular mass index but reduced cardiac fibrosis by 50% (P<0.01) through modulating collagen I expression, reversed by PD123 319 coinfusion. In addition, angiotensin-(1-9) inhibited fibroblast proliferation in vitro in a PD123 319-sensitive manner. Aortic myography revealed that angiotensin-(1-9) significantly increased contraction to phenylephrine compared with controls after N-nitro-l-arginine methyl ester treatment, an effect abolished by PD123 319 coinfusion (area under the curve: angiotensin-(1-9) N-nitro-l-arginine methyl ester=98.9±11.8%; control+N-nitro-l-arginine methyl ester=74.0±10.4%; P<0.01), suggesting that angiotensin-(1-9) improved basal NO bioavailability in an angiotensin type 2 receptor-sensitive manner. In summary, angiotensin-(1-9) reduced cardiac fibrosis and altered aortic contraction via the angiotensin type 2 receptor supporting a direct role for angiotensin-(1-9) in the renin-angiotensin system.

Original languageEnglish
Pages (from-to)300-7
Number of pages8
JournalHypertension
Volume59
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Angiotensin I
  • Angiotensin II Type 2 Receptor Blockers
  • Animals
  • Blood Pressure
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Echocardiography
  • Endothelium, Vascular
  • Fibroblasts
  • Fibrosis
  • Heart
  • Hypertension
  • Imidazoles
  • In Vitro Techniques
  • Male
  • Myocardium
  • Peptide Fragments
  • Pyridines
  • Rats
  • Receptor, Angiotensin, Type 2
  • Renin-Angiotensin System
  • Stroke

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