Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1

作者：Zhu Liping; Carretero Oscar A; Xu Jiang; Wang Luchen; Harding Pamela; Rhaleb Nour Eddine; Yang James J; Sumners Colin; Yang Xiao Ping^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2012, 302(12): H2553-H2559.

DOI：10.1152/ajpheart.01157.2011

• prolylcarboxypeptidase
• plasma kallikrein-kinin system

Zhu L, Carretero OA, Xu J, Wang L, Harding P, Rhaleb NE, Yang JJ, Sumners C, Yang XP. Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1. Am J Physiol Heart Circ Physiol 302: H2553-H2559, 2012. First published April 20, 2012; doi:10.1152/ajpheart.01157.2011.-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.

• 出版日期2012-6