title: Angiotensin (1-7) counteracts the negative effect of angiotensin II on insulin signalling in HUVECs.
abstract: OBJECTIVE
  Angiotensin II participates to the regulation of cardiovascular physiology and it is involved in molecular mechanisms of insulin resistance. Angiotensin (1-7), derived from angiotensin II metabolism, is able to counteract many of the haemodynamic and non-haemodynamic actions of angiotensin II. In this study, we investigated in human umbilical vein endothelial cells (HUVECs) the possible action of angiotensin (1-7) on the insulin signalling pathway.
  
  
  RESULTS
  We stimulated HUVECs with insulin, angiotensin II and angiotensin (1-7), testing the effects on endothelial nitric oxide synthase (eNOS) enzyme activation and on insulin receptor substrate-1 (IRS1) phosphorylation. Moreover, we analysed the involvement of angiotensin type1, type2, and Mas receptors in these actions. Finally, we measured the nitric oxide (NO) production, the intracellular cGMP and the PKG-related activity in HUVECs, and the subsequent functional vasoactive effect of angiotensin (1-7) in mesenteric arteries of mice. Angiotensin II inhibits the insulin-induced Akt and eNOS phosphorylation, reducing the NO production. On the other hand, angiotensin (1-7) counteracts the inhibitory effect of angiotensin II, being able to restore the insulin-induced Akt/eNOS activation and the NO production. This effect is mediated by the Mas receptor. The inhibitory effects of angiotensin II on insulin signalling are, at least in part, mediated by an increased serine phosphorylation of IRS₁. Angiotensin (1-7) inhibits the serine phosphorylation of IRS1 induced by angiotensin II.
  
  
  CONCLUSIONS
  In endothelial cells angiotensin (1-7) counteracts the negative effects of angiotensin II on insulin signalling and NO production. The balance between angiotensin II and angiotensin (1-7) could represent a key mechanism in the pathophysiological processes leading to endothelial dysfunction and insulin-resistance.
authors.affiliation: Department of Surgical and Medical Sciences, University Magna Græcia of Catanzaro, Campus Universitario di Germaneto, V.le Europa, 88100 Catanzaro, Italy.
authors.forename: Eliezer Joseph
authors.initials: EJ
authors.lastname: Tassone
authors.forename: Angela
authors.initials: A
authors.lastname: Sciacqua
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.forename: Ivan
authors.initials: I
authors.lastname: Presta
authors.forename: Maria
authors.initials: M
authors.lastname: Perticone
authors.forename: Daniela
authors.initials: D
authors.lastname: Carnevale
authors.forename: Manuel
authors.initials: M
authors.lastname: Casaburo
authors.forename: Marta Letizia
authors.initials: ML
authors.lastname: Hribal
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.forename: Francesco
authors.initials: F
authors.lastname: Perticone
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008638:Mesenteric Arteries / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D014664:Vasodilation
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D009569:Nitric Oxide; D000803:Angiotensin I; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; C118790:angiotensin I (1-7)
keywords: Angiotensin (1–7); Endothelium; Insulin; Nitric oxide