Angiotensin‐(1–7) has a dual role on growth‐promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II‐stimulated ERK1/2 and Rho kinase activity

Angiotensin (ANG) II contributes to cardiac remodelling by inducing the activation of several signalling molecules, including ERK1/2, Rho kinase and members of the STAT family of proteins. Angiotensin‐(1–7) is produced in the heart and inhibits the proliferative actions of ANG II, although the mechanisms of this inhibition are poorly understood. Accordingly, in the present study we examined whether ANG‐(1–7) affects the ANG II‐mediated activation of ERK1/2 and Rho kinase, STAT3 and STAT5a/b in rat heart in vivo . We hypothesized that ANG‐(1–7) inhibits these growth‐promoting pathways, counterbalancing the trophic action of ANG II. Solutions of normal saline (0.9% NaCl) containing ANG II (8 pmol kg −1 ) plus ANG‐(1–7) in increasing doses (from 0.08 to 800 pmol kg −1 ) were administered via the inferior vena cava to anaesthetized male Sprague–Dawley rats. After 5 min, hearts were removed and ERK1/2, Rho kinase, STAT3 and STAT5a/b phosphorylation was determined by Western blotting using phosphospecific antibodies. Angiotensin II stimulated ERK1/2 and Rho kinase phosphorylation (2.3 ± 0.2‐ and 2.1 ± 0.2‐fold increase over basal values, respectively), while ANG‐(1–7) was without effect. The ANG II‐mediated phosphorylation of ERK1/2 and Rho kinase was prevented in a dose‐dependent manner by ANG‐(1–7) and disappeared in the presence of the Mas receptor antagonist d ‐Ala 7 ‐ANG‐(1–7). Both ANG II and ANG‐(1–7) increased STAT3 and STAT5a/b phosphorylation to a similar extent (130–140% increase). The ANG‐(1–7)‐stimulated STAT phosphorylation was blocked by the AT 1 receptor antagonist losartan and not by d ‐Ala 7 ‐ANG‐(1–7). Our results show a dual action of ANG‐(1–7), that is, a stimulatory effect on STAT3 and 5a/b phosphorylation through AT 1 receptors and a blocking action on ANG II‐stimulated ERK1/2 and Rho kinase phosphorylation through Mas receptor activation. The latter effect could be representative of a mechanism for a protective role of ANG‐(1–7) in the heart by counteracting the effects of locally generated ANG II.