title: Transactivation of ErbB Family of Receptor Tyrosine Kinases Is Inhibited by Angiotensin-(1-7) via Its Mas Receptor.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait.
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait.
authors.forename: Bindu
authors.initials: B
authors.lastname: Chandrasekhar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait.
authors.forename: Sreeja
authors.initials: S
authors.lastname: Attur
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait.
authors.forename: Gursev S
authors.initials: GS
authors.lastname: Dhaunsi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait.
authors.forename: Mariam H M
authors.initials: MH
authors.lastname: Yousif
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait.
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D014665:Vasodilator Agents; D000803:Angiotensin I; D066246:ErbB Receptors; C118790:angiotensin I (1-7); D005947:Glucose