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.

Año: 2007

0958-0670

Exp Physiol. 2008 Jan 11 [Epub ahead of print] Links 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. QUIFIB, Facultad de Farmacia y Bioquímica, UBA. Angiotensin (ANG) II contributes to cardiac remodeling by inducing the activation of several signaling molecules including ERK1/2, Rho-kinase and members of the STAT family of proteins. ANG-(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 current study we examined whether ANG-(1-7) affects the ANG II-mediated ERK1/2, STAT3 and 5a/b as well as Rho-kinase activation in the rat heart in vivo. We hypothesize 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) plus ANG-(1-7) in increasing doses (0.08-800 pmol/Kg) were administered via vena cava to male Sprague-Dawley rats. After 5 min, hearts were isolated and ERK1/2, Rho-kinase, STAT 3 and 5a/b phosphorylation was determined by Western Blotting using phosphospecific antibodies. ANG II stimulated ERK1/2 and Rho-kinase phosphorylation (2.3 +/- 0.2-fold increase and 2.1 +/- 0.2-fold increase over basal, respectively), while Ang-(1-7) was without effect. The ANG II-mediated phosphorylation of ERK 1/2 and Rho-kinase was dose-dependently prevented 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 a/b phosphorylation through AT1 receptors and a blocking action on ANG II-stimulated ERK1/2 and Rho kinase phosphorylation through mas receptor activation. This last 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.