Angiotensin-(1-7) has a dual role on growth-promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II-stimulated ERK1/2 and Rho kinase activity.
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 AT(1) 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 AT(1) 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.
Giani
Jorge F
JF
Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
Gironacci
Mariela M
MM
Muñoz
Marina C
MC
Turyn
Daniel
D
Dominici
Fernando P
FP
D000803:Angiotensin I / Q000494:pharmacology / Q000502:physiology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D006128:Growth / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494088:Stat3 protein, rat; C494094:Stat5a protein, rat; C494097:Stat5b protein, rat; D000804:Angiotensin II; D014443:Tyrosine; D000803:Angiotensin I; D054460:rho-Associated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C118790:angiotensin I (1-7)