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

Abstract

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 (AT2R) 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 AT2R 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 AT2R-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 AT2R using the specific agonist CGP42112A increased SHP-1 activity in ECs, which was blocked by the AT2R antagonist PD123319. Activation of AT2R 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 AT2R-stimulated prekallikrein activation and bradykinin release. Furthermore, blocking plasma kallikrein with soybean trypsin inhibitor (SBTI) abolished AT2R-stimulated bradykinin release. These findings support our hypothesis that stimulation of AT2R activates a PRCP-dependent plasma prekallikrein pathway, releasing bradykinin. Activation of SHP-1 may also play an important role in AT2R-induced PRCP activation.prolylcarboxypeptidase; plasma kallikrein-kinin system ANGIOTENSIN II (ANG II) is classically considered a vasoconstrictor and pro-growth molecule acting via the ANG II type 1 receptor (AT 1 R). Although the role of AT 2 R remains controversial, they are generally thought to be mutually antagonistic, with AT 2 R opposing the actions of AT 1 R (6, 14, 21). Some of the beneficial effects of AT 2 R are mediated by bradykinin/ nitric oxide (NO) (5, 10), and overexpression of AT 2 R in the vasculature reportedly stimulated the kinin system, causing dilatation (31). Likewise cardiac AT 2 R overexpression attenuated fibrosis induced by ANG II or myocardial infarction, apparently acting via a kinin/NO-dependent mechanism (3, 7). We have demonstrated that the cardioprotective effects of AT 1 R antagonists are mediated in part by activation of AT 2 R and kinins, since they were diminished in AT 2 R or kinin receptors knock out mice and kinin-deficient rats or by blocking the AT 2 R or kinin receptors (11, 34 -36). However, the precise mechanism(s) by which AT 2 R mediates kinin release is not yet known.Prolylcarboxypeptidase (PRCP) is a serine carboxypeptidase that cleaves a variety of COOH-terminal amino acids adjacent to proline and has been linked to hypertension and preeclampsia (1, 32) as well as obesity (23). Dysfunction of PRCP is associ...

Plasma Kallikrein Inhibitors in Cardiovascular Disease

“…138 Stimulation of AT 2 receptors has been shown to increase prolylcarboxypeptidase-dependent PK activation. 139 In addition to these effects, studies have shown that the AT 1 and B 2 receptors interact at a more fundamental level. The AT 1 and B 2 receptors form stable heterodimers causing increased activation of Gαq-and Gαi-proteins, change in endocytic pathways of both receptors, and a four-to fivefold increase in protein levels of B 2 receptors.…”

“…139,144 Bradykinin-induced vasodilation has been attributed to the activation of bradykinin receptors on the endothelium. In contrast, bradykinin, via its effects on the central nervous system, has been shown to elevate blood pressure via the B 2 receptors and to induce a cardiac sympathetic response.…”

Arterial Hypertension in Systemic Vasculitis: Clinical Features and Principles of Pathogenetic Therapy. Part Ii. Possibilities of Optimizing of Antihypertensive Treatment

“…В основе фармакологического эффекта препаратов данной группы лежит блокада ан-гиотензиновых рецепторов 1 типа при сохранении влияния стимулирующего эффекта ангиотензина II на рецепторы 2 типа [20]. Предполагается, что именно аго-низм в отношении ангиотензиновых рецепторов 2 типа позволяет реализовать кардиопротективные и вазопротективные эффекты сартанам, однако в по-следние годы продемонстрирована возможность сти-муляции данными фармакологическими агентами брадикининовых В1-рецепторов, что в свою очередь подавляет провоспалительные механизмы и повыша-ет экскрецию оксида азота [21,22]. Среди антигипер-тензивных средств сартаны рассматриваются в числе наиболее эффективных и, что весьма важно, наиболее безопасных [23] препаратов.…”

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

“…There is consistent experimental evidence indicating that the cardiovascular and renal effects of ACE inhibitors, including in diabetes, are due in large part to kinins (Liu et al 2000, Griol-Charhbili et al 2005, Buleon et al 2008. Similarly, angiotensin II AT1 receptor blockade induces renin secretion and AT2 receptor activation, which triggers tissue kallikrein (TK) or plasma kallikreinmediated kinin release and kinin receptor activation (Zhu et al 2012). Cardiac, vascular, and renal effects of AT1 receptor blockers, like those of ACE inhibitors, are suppressed experimentally by pharmacological or genetic inactivation of TK, the main kinin-forming enzyme, or kinin receptors.…”