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

• Published in: Endocrinology (Philadelphia) Vol. 144; no. 12; pp. 5604 - 5614
• Main Authors: Carvalheira, José B. C, Calegari, Vivian C, Zecchin, Henrique G, Nadruz, Wilson, Guimarães, Regina B, Ribeiro, Eliane B, Franchini, Kleber G, Velloso, Lício A, Saad, Mario J. A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.12.2003
• Subjects: Adaptor Proteins, Signal Transducing; Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; GRB2 Adaptor Protein; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance - physiology; Janus Kinase 2; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Myocardium - metabolism; Obesity - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Rats, Zucker; Receptor Cross-Talk - physiology; Vasoconstrictor Agents - metabolism; Vasoconstrictor Agents - pharmacology; Vertebrates: endocrinology; Heart; Pancreatic hormone; Rat; Enzyme; Rodentia; Mitogen-activated protein kinase; Insulin; Target tissue resistance; Signal transduction; Renin angiotensin system; Vertebrata; Mammalia; Animal; Angiotensin; Circulatory system; Phosphatidylinositol 3-kinase
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0788

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.