Angiotensin-(1-7) counteracts angiotensin II signaling in rat heart

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

Ouro Preto, Minas Gerais, Brasil.

Simposio; Vasoactive Peptides - VII International Symposium; 2008

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 (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-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 theAT1 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.