Angiotensin (ANG)-(1-7) elicits a dual role on growth-promoting signaling pathways in rat heart in vivo by stimulating STAT3 and 5a/b phosphorylation and inhibiting ANG II-stimulated ERK1/2 and Rho-kinase activity.

GIANI JF; GIRONACCI MM; MUÑOZ MC; TURYN D; DOMINICI FP

EXPERIMENTAL PHYSIOLOGY.

Blackwell Publishing

Lugar: Londres, Reino Unido; 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 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-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 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.