Angiotensin-(1-9) Attenuates Cardiac Fibrosis in the Stroke-Prone Spontaneously Hypertensive Rat via the Angiotensin Type 2 Receptor

Abstract

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% (PϽ0.01) 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 esterϭ98.9Ϯ11.8%; controlϩN-nitro-Larginine methyl esterϭ74.0Ϯ10.4%; PϽ0.01), 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 reninangiotensin system. (Hypertension. 2012;59:300-307.) • Online Data Supplement Key Words: renin-angiotensin system Ⅲ angiotensin-(1-9) Ⅲ cardiac fibrosis Ⅲ angiotensin type 2 receptor Ⅲ stroke-prone spontaneously hypertensive rat A ngiotensin II (Ang II) is the main effector of the renin-angiotensin system (RAS), classically acting via the angiotensin type 1 receptor (AT 1 R) to stimulate effects such as sodium reabsorption, vasoconstriction, proliferation, and inflammation. Ang II, acting via the AT 1 R, contributes to the pathophysiology of cardiovascular disease. The angiotensin type 2 receptor (AT 2 R) is 34% homologous to the AT 1 R, 1 and its actions differ. 2,3 AT 2 R expression is limited to fetal/neonatal tissues 4 ; however, in adult rodents it is upregulated in heart failure and postmyocardial infarction. 5 In human adult myocardium, 41% of angiotensin binding sites are AT 2 Rs. 5 Ang II signaling via the AT 2 R counteracts AT 1 R signaling; for example, blocking AT 2 R activation promotes cardiomyocyte hypertrophy, 2 whereas AT 2 R overexpression in stroke-p...

El efecto anti-hipertensivo de Angiotensina-(1-9) es mediado por aumento temprano de la diuresis y natriuresis

“…Por lo tanto, el eje del SRA a través de la ECA2 y de Ang-(1-9) podría ser un importante blanco terapéutico de la HTA. Recientemente, Flores-Muñoz et al, mostró en su modelo experimental de ratas "strole-prone" espontáneamente hipertensas (SPSHR) que Ang-(1-9) administrada en dosis de 100 ng·Kg-1·min-1 no modificó la PAS 22 . Estos resultados difieren del efecto antihipertensivo observado para Ang-(1-9) probablemente, debido a la menor dosis de Ang-(1-9) usada en ratas SPSHR comparada con nuestros estudios de regresión de la HTA 23 .…”

“…Ambos efectos estuvieron directamente relacionados a la administración de Ang-(1-9) y no mediados por Ang-(1-7). Éstos resultados son consistentes con estudios publicados que muestran que la admistración de Ang-(1-9) a ratas SPSHR disminuyó la fibrosis cardíaca 22 . El efecto antifibrótico fue bloqueado por el antagonista del AT2R.…”

“…Además, Ang-(1-9) inhibió la proliferación de fibroblastos in vitro, cuyo efecto fue sensible al antagonista del AT2R, PD123319. Estos resultados muestran que la activación del AT2R por Ang-(1-9) tiene un importante efecto antifibrótico que puede implicar una acción directa sobre los fibroblastos 22 . En relación al mecanismo de acción de Ang-(1-9), antecedentes previos señalan que ésta presenta propiedades vasoactivas al aumentar los niveles de eNOS y nitratos plasmáticos, sugiriendo que las acciones vasodilatadoS-RA de Ang-(1-9) estarían mediadas por un incremento de Óxido Nítrico (NO, potente vasodilatador) 25 .…”

“…En relación al mecanismo de acción de Ang-(1-9), antecedentes previos señalan que ésta presenta propiedades vasoactivas al aumentar los niveles de eNOS y nitratos plasmáticos, sugiriendo que las acciones vasodilatadoS-RA de Ang-(1-9) estarían mediadas por un incremento de Óxido Nítrico (NO, potente vasodilatador) 25 . Además, ha sido descrito que Ang-(1-9) potencia la liberación de bradicinina en células endoteliales aisladas de tejido cardíaco, lo que se relaciona con el aumento de la biodisponibilidad de NO en las células endoteliales 22 . Cuando las células endoteliales son tratadas con Ang-(1-9) y PD123,3 19 (Antagonista del receptor AT2) disminuye la biodisponibilidad de los niveles de NO en los animales de control 22 .…”

Effects of apelin on the cardiovascular system

“…Angiotensin 1-9 exerts beneficial effects on the heart, which consist in reduction of blood pressure, improvement of endothelial function and limitation of hypertrophy and fibrosis [38]. It has been suggested that these beneficial effects of Ang 1-9 can be achieved via angiotensin II type 2 receptor (AT2R), independently of its conversion to Ang 1-7 [38,39]. In addition to the favorable activity on cardiac dysfunction, ACE2 was reported to play a role in the hydrolysis of a large number of peptides, including apelin-13 and apelin-36, which are thus degraded to ineffective forms [40].…”