Back to Search
Start Over
Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2012 Jun 15; Vol. 302 (12), pp. H2553-9. Date of Electronic Publication: 2012 Apr 20. - Publication Year :
- 2012
-
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.
- Subjects :
- Animals
Cells, Cultured
Coronary Vessels cytology
Coronary Vessels drug effects
Coronary Vessels metabolism
Endothelial Cells cytology
Endothelial Cells drug effects
Endothelium, Vascular cytology
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Mice
Oligopeptides pharmacology
RNA, Small Interfering
Bradykinin metabolism
Endothelial Cells metabolism
Prekallikrein metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism
Receptor, Angiotensin, Type 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 302
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 22523247
- Full Text :
- https://doi.org/10.1152/ajpheart.01157.2011