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

Authors: Flores-Munoz, M  Work, LM  Douglas, K  Denby, L  Dominiczak, AF  Graham, D  Nicklin, SA 
Citation: Flores-Munoz M, etal., Hypertension. 2012 Feb;59(2):300-7. Epub 2011 Dec 19.
Pubmed: (View Article at PubMed) PMID:22184331
DOI: Full-text: DOI:10.1161/HYPERTENSIONAHA.111.177485

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.

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CRRD Object Information
CRRD ID: 6903874
Created: 2012-10-04
Species: All species
Last Modified: 2012-10-04
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.