title: Angiotensin-(1 7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT1 and Mas receptors.
abstract: Angiotensin (ANG) II exerts a negative modulation on insulin signal transduction that might be involved in the pathogenesis of hypertension and insulin resistance. ANG-(1-7), an endogenous heptapeptide hormone formed by cleavage of ANG I and ANG II, counteracts many actions of ANG II. In the current study, we have explored the role of ANG-(1-7) in the signaling crosstalk that exists between ANG II and insulin. We demonstrated that ANG-(1-7) stimulates the phosphorylation of Janus kinase 2 (JAK2) and insulin receptor substrate (IRS)-1 in rat heart in vivo. This stimulating effect was blocked by administration of the selective ANG type 1 (AT(1)) receptor blocker losartan. In contrast to ANG II, ANG-(1-7) stimulated cardiac Akt phosphorylation, and this stimulation was blunted in presence of the receptor Mas antagonist A-779 or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The specific JAK2 inhibitor AG-490 blocked ANG-(1-7)-induced JAK2 and IRS-1 phosphorylation but had no effect on ANG-(1-7)-induced phosphorylation of Akt, indicating that activation of cardiac Akt by ANG-(1-7) appears not to involve the recruitment of JAK2 but proceeds through the receptor Mas and involves PI3K. Acute in vivo insulin-induced cardiac Akt phosphorylation was inhibited by ANG II. Interestingly, coadministration of insulin with an equimolar mixture of ANG II and ANG-(1-7) reverted this inhibitory effect. On the basis of our present results, we postulate that ANG-(1-7) could be a positive physiological contributor to the actions of insulin in heart and that the balance between ANG II and ANG-(1-7) could be relevant for the association among insulin resistance, hypertension, and cardiovascular disease.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Tecnológicas, Buenos Aires, Argentina.
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Giani
authors.forename: Mariela M
authors.initials: MM
authors.lastname: Gironacci
authors.forename: Marina C
authors.initials: MC
authors.lastname: Muñoz
authors.forename: Clara
authors.initials: C
authors.lastname: Peña
authors.forename: Daniel
authors.initials: D
authors.lastname: Turyn
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Dominici
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000803:Angiotensin I; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D053614:Janus Kinase 2; D019808:Losartan; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D020032:Tyrphostins; D000077191:Wortmannin; C092006:7-Ala-angiotensin (1-7); C526296:Irs1 protein, rat; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507927:Jak2 protein, rat; C118790:angiotensin I (1-7)