title: The cross-talk between angiotensin and insulin differentially affects phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-mediated signaling in rat heart: implications for insulin resistance.
abstract: Insulin and angiotensin II (AngII) may act through overlapping intracellular pathways to promote cardiac myocyte growth. In this report insulin and AngII signaling, through the phosphatidylinositol 3-kinase (PI 3-kinase) and MAPK pathways, were compared in cardiac tissues of control and obese Zucker rats. AngII induced Janus kinase 2 tyrosine phosphorylation and coimmunoprecipitation with insulin receptor substrate 1 (IRS-1) and IRS-2 as well as an increase in tyrosine phosphorylation of IRS and its association with growth factor receptor-binding protein 2. Simultaneous treatment with both hormones led to marked increases in the associations of IRS-1 and -2 with growth factor receptor-binding protein 2 and in the dual phosphorylation of ERK1/2 compared with the administration of AngII or insulin alone. In contrast, an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity was induced by both hormones. Insulin stimulated the phosphorylation of MAPK equally in lean and obese rats. Conversely, insulin-induced phosphorylation of Akt in heart was decreased in obese rats. Pretreatment with losartan did not change insulin-induced activation of ERK1/2 and attenuated the reduction of Akt phosphorylation in the heart of obese rats. Thus, the imbalance between PI 3-kinase-Akt and MAPK signaling pathways in the heart may play a role in the development of cardiovascular abnormalities observed in insulin-resistant states, such as in obese Zucker rats.
authors.affiliation: Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Campinas, São Paulo 13081-970, Brazil.
authors.forename: José B C
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Vivian C
authors.initials: VC
authors.lastname: Calegari
authors.forename: Henrique G
authors.initials: HG
authors.lastname: Zecchin
authors.forename: Wilson
authors.initials: W
authors.lastname: Nadruz
authors.forename: Regina B
authors.initials: RB
authors.lastname: Guimarães
authors.forename: Eliane B
authors.initials: EB
authors.lastname: Ribeiro
authors.forename: Kleber G
authors.initials: KG
authors.lastname: Franchini
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D051380:GRB2 Adaptor Protein; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D053614:Janus Kinase 2; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D020239:Receptor Cross-Talk / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II; D051380:GRB2 Adaptor Protein; D007004:Hypoglycemic Agents; D007328:Insulin; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014662:Vasoconstrictor Agents; C495950:Grb2 protein, rat; C507927:Jak2 protein, rat; C494920:Akt1 protein, rat