title: Angiotensin-(1-9) attenuates cardiac fibrosis in the stroke-prone spontaneously hypertensive rat via the angiotensin type 2 receptor.
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.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, 126 University Pl, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Flores-Munoz
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Work
authors.forename: Kirsten
authors.initials: K
authors.lastname: Douglas
authors.forename: Laura
authors.initials: L
authors.lastname: Denby
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005355:Fibrosis; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology; D020521:Stroke / Q000517:prevention & control*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D010446:Peptide Fragments; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C506331:angiotensin I (1-9); C073402:PD 123319; D000803:Angiotensin I