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This Article Full Text Full Text (PDF) All Versions of this Article: 93/5/570    most recent expphysiol.2007.041269v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Giani, J. F. Articles by Dominici, F. P. PubMed PubMed Citation Articles by Giani, J. F. Articles by Dominici, F. P. Related Collections Heart/Cardiac Muscle

¹ Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica,Universidad de Buenos Aires, Argentina

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.

(Received 1 November 2007; accepted after revision 9 January 2008; first published online 11 January 2008)
Corresponding author F. P. Dominici: Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Capital Federal, 1113, Argentina. Email: dominici{at}qb.ffyb.uba.ar