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.

GIANI JF, GIRONACCI MM, MUÑOZ MC, TURYN D, DOMINICI FP.

EXPERIMENTAL PHYSIOLOGY.

WILEY-BLACKWELL PUBLISHING, INC

Año: 2008 vol. 93 p. 570 - 578

0958-0670

Angiotensin (ANG) II contributes to cardiac remodelling by inducing the activation of several signalling molecules, including ERK1/2, Rho kinase and members of the STATfamily 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 (from0.08 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-mediatedphosphorylationofERK1/2andRhokinasewaspreventedinadose-dependent manner by ANG-(1?7) and disappeared in the presence of the Mas receptor antagonist D-Ala7-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 AT1 receptor antagonist losartan and not by D-Ala7-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 AT1 receptors and a blocking action on ANG II-stimulated ERK1/2 and Rho kinase phosphorylation throughMas 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.