Transactivation of ErbB Family of Receptor Tyrosine Kinases Is Inhibited by Angiotensin-(1-7) via Its Mas Receptor

• Published in: PloS one 2015-11, Vol.10 (11), p.e0141657
• Main Authors: Akhtar, Saghir, Chandrasekhar, Bindu, Attur, Sreeja, Dhaunsi, Gursev S, Yousif, Mariam H M, Benter, Ibrahim F
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin I - pharmacology; Angiotensin II; Angiotensins; Animals; Apoptosis; Blotting, Western; Cells, Cultured; Complications; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; ErbB protein; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB-2 protein; ErbB-3 protein; Extracellular signal-regulated kinase; Gene Expression Regulation - drug effects; Glucose; Glucose - metabolism; Hyperglycemia; Hypertension; Inhibitors; Kinases; Laboratory animals; Ligands; Male; MAP kinase; Medicine; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscles; Nitric oxide; Noradrenaline; Norepinephrine; Peptide Fragments - pharmacology; Pharmacology; Phenols (Class of compounds); Phosphorylation; Phosphotransferases; Proteins; Proto-Oncogene Proteins - metabolism; Rats; Rats, Wistar; Receptors; Receptors, G-Protein-Coupled - metabolism; Rodents; Signal Transduction; Smooth muscle; Streptozocin; Toxicology; Transcriptional Activation - drug effects; Tyrosine; Vasodilator Agents - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141657

Transactivation of the epidermal growth factor receptor (EGFR or ErbB) family members, namely EGFR and ErbB2, appears important in the development of diabetes-induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] can prevent the development of hyperglycemia-induced vascular complications partly through inhibiting EGFR transactivation. Here, we investigated whether Ang-(1-7) can inhibit transactivation of ErbB2 as well as other ErbB receptors in vivo and in vitro. Streptozotocin-induced diabetic rats were chronically treated with Ang-(1-7) or AG825, a selective ErbB2 inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in cultured vascular smooth muscle cells (VSMCs). Ang-(1-7) or AG825 treatment inhibited diabetes-induced phosphorylation of ErbB2 receptor at tyrosine residues Y1221/22, Y1248, Y877, as well as downstream signaling via ERK1/2, p38 MAPK, ROCK, eNOS and IkB-α in the mesenteric vascular bed. In VSMCs cultured in high glucose (25 mM), Ang-(1-7) inhibited src-dependent ErbB2 transactivation that was opposed by the selective Mas receptor antagonist, D-Pro7-Ang-(1-7). Ang-(1-7) via Mas receptor also inhibited both Angiotensin II- and noradrenaline/norephinephrine-induced transactivation of ErbB2 and/or EGFR receptors. Further, hyperglycemia-induced transactivation of ErbB3 and ErbB4 receptors could be attenuated by Ang-(1-7) that could be prevented by D-Pro7-Ang-(1-7) in VSMC. These data suggest that Ang-(1-7) via its Mas receptor acts as a pan-ErbB inhibitor and might represent a novel general mechanism by which Ang-(1-7) exerts its beneficial effects in many disease states including diabetes-induced vascular complications.