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Angiotensin‐(1‐7) inhibits epidermal growth factor receptor transactivation via a Mas receptor‐dependent pathway
Author(s) -
Akhtar Saghir,
Yousif Mariam HM,
Dhaunsi Gursev S,
Chandrasekhar Bindu,
AlFarsi Omama,
Benter Ibrahim F
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01613.x
Subject(s) - transactivation , endocrinology , medicine , angiotensin ii , receptor , mapk/erk pathway , epidermal growth factor , receptor antagonist , proto oncogene tyrosine protein kinase src , insulin like growth factor 1 receptor , epidermal growth factor receptor , chemistry , signal transduction , biology , microbiology and biotechnology , growth factor , antagonist , biochemistry , gene , transcription factor
BACKGROUND AND PURPOSE The transactivation of the epidermal growth factor (EGF) receptor appears to be an important central transduction mechanism in mediating diabetes‐induced vascular dysfunction. Angiotensin‐(1‐7) [Ang‐(1‐7)] via its Mas receptor can prevent the development of hyperglycaemia‐induced cardiovascular complications. Here, we investigated whether Ang‐(1‐7) can inhibit hyperglycaemia‐induced EGF receptor transactivation and its classical signalling via ERK1/2 and p38 MAPK in vivo and in vitro . EXPERIMENTAL APPROACH Streptozotocin‐induced diabetic rats were chronically treated with Ang‐(1‐7) or AG1478, a selective EGF receptor inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in primary cultures of vascular smooth muscle cells (VSMCs). KEY RESULTS Diabetes significantly enhanced phosphorylation of EGF receptor at tyrosine residues Y992, Y1068, Y1086, Y1148, as well as ERK1/2 and p38 MAPK in the mesenteric vasculature bed whereas these changes were significantly attenuated upon Ang‐(1–7) or AG1478 treatment. In VSMCs grown in conditions of high glucose (25 mM), an Src‐dependent elevation in EGF receptor phosphorylation was observed. Ang‐(1‐7) inhibited both Ang II‐ and glucose‐induced transactivation of EGF receptor. The inhibition of high glucose‐mediated Src‐dependant transactivation of EGF receptor by Ang‐(1‐7) could be prevented by a selective Mas receptor antagonist, D‐Pro7‐Ang‐(1‐7). CONCLUSIONS AND IMPLICATIONS These results show for the first time that Ang‐(1‐7) inhibits EGF receptor transactivation via a Mas receptor/Src‐dependent pathway and might represent a novel general mechanism by which Ang‐(1‐7) exerts its beneficial effects in many disease states including diabetes‐induced vascular dysfunction.