title: Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1.
abstract: ANG II type 2 receptors (AT(2)R) elicit cardioprotective effects in part by stimulating the release of kinins; however, the mechanism(s) responsible have not been fully explored. We demonstrated previously that overexpression of AT(2)R increased expression of prolylcarboxypeptidase (PRCP; a plasma prekallikrein activator) and release of bradykinin by mouse coronary artery endothelial cells (ECs). In the present study we hypothesized that the AT(2)R-stimulated increase in PRCP is mediated by the tyrosine phosphatase SHP-1, which in turn activates the PRCP-dependent prekallikrein-kallikrein pathway and releases bradykinin. We found that activation of AT(2)R using the specific agonist CGP42112A increased SHP-1 activity in ECs, which was blocked by the AT(2)R antagonist PD123319. Activation of AT(2)R also enhanced conversion of plasma prekallikrein to kallikrein, and this effect was blunted by a small interfering RNA (siRNA) to SHP-1 and abolished by the tyrosine phosphatase inhibitor sodium orthovanadate. Treating cells with a siRNA to PRCP also blunted AT(2)R-stimulated prekallikrein activation and bradykinin release. Furthermore, blocking plasma kallikrein with soybean trypsin inhibitor (SBTI) abolished AT(2)R-stimulated bradykinin release. These findings support our hypothesis that stimulation of AT(2)R activates a PRCP-dependent plasma prekallikrein pathway, releasing bradykinin. Activation of SHP-1 may also play an important role in AT(2)R-induced PRCP activation.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202-2689, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhu
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.forename: Luchen
authors.initials: L
authors.lastname: Wang
authors.forename: Pamela
authors.initials: P
authors.lastname: Harding
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D011288:Prekallikrein / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D034741:RNA, Small Interfering; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; D034741:RNA, Small Interfering; D044139:Receptor, Angiotensin, Type 2; C060894:CGP 42112A; D011288:Prekallikrein; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D001920:Bradykinin