Received November 1, 2007
Revised November 26, 2007
Accepted after revision January 9, 2008
Heart/Cardiac Muscle [240]
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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
Jorge F Giani 1,
Mariela M Gironacci 1,
Marina C Muñoz 1,
Daniel Turyn 1,
Fernando P Dominici 1*
1 QUIFIB, Facultad de Farmacia y Bioquímica, UBA
* To whom correspondence should be addressed. E-mail: dominici{at}qb.ffyb.uba.ar.
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Abstract |
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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.
Key Words:
Angiotensin, Cell signalling, Heart
