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.

Angiotensin 1–7 Is a Negative Modulator of Aldosterone Secretion In Vitro and In Vivo

“…23 Furthermore, recent evidence suggests that signaling through Mas1 can inhibit AT1R-dependent transactivation of epidermal growth factor receptor. 24 However, whether inhibition of this pathway plays a role in Ang 1-7-dependent inhibition of receptor activated aldosterone secretion remains to be directly studied.…”

Transactivation of Epidermal Growth Factor Receptor by G Protein-Coupled Receptors: Recent Progress, Challenges and Future Research

“…In cultured vascular smooth muscle cells, Ang II and glucose induce the transactivation of EGFR, however, this transactivation is attenuated by angitensin-(1–7) via the activation of Mas receptor [ 77 ]. They later showed that Ang-(1–7) acts as a pan-ErbB inhibitor via its Mas receptor [ 78 ]. It is well established that GPCR transactivates EGFR through Src, this is the first report that GPCR/Src pathway is involved in the inhibition of EGFR transactivation by other GPCRs.…”

Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety

“…We have shown that activation of this beneficial pathway endogenously or exogenously by administering Ang-(1-7) or its analog prevents or improves the multiple diabetes-induced complications [21,34,37,[125][126][127] including some through inhibiting the transactivation of EGFR/ErbB receptors [128,129]. In models of diabetes and/or hypertension, we have shown that administering Ang-(1-7) prevented endothelial dysfunction, cardiac and renal end-organ damage via mechanisms involving inhibition of NADPH oxidase, NF-kB, TLR-2, IRAK-1, IL-6, EGFR receptors, and renal TGF-beta [32,40,128,129] or activation of NO, catalase and PPAR-gamma pathways [34,130]. It should be noted here, that activation of ACE2-Ang-(1-7) pathway has little or no effects on normal/healthy animals but displays its beneficial anti-pressor effects or cardiovascular benefits only in models of disease e.g.…”