Activation of the Plasma Kallikrein / Kinin System on Endothelial Cells

Abstract

For more than two decades, it has been known that activation of the plasma kallikrein/kinin system only occurs when it is exposed to artificial, negatively charged surfaces. The existence of physiological, negatively charged surfaces has, however, never been demonstrated in vivo. In this report, we describe current knowledge about how the proteins of the plasma kallikrein/kinin system interact with and become activated on cell membranes. In this model, activation of the plasma kallikrein/kinin system on endothelial cells is not initiated by factor XII autoactivation, as seen on artificial surfaces. On endothelial cells, plasma prekallikrein is activated by a membrane-associated cysteine protease. This activation is dependent on the presence of high molecular weight kininogen and an optimal zinc (Zn2+) concentration. Although the initiation of activation of plasma prekallikrein is independent of factor XII, kallikrein-mediated factor XIIa generation, in turn, accelerates the activation of the system. Further kallikrein formed on endothelial cell membranes is capable of cleaving its receptor and native substrate, high molecular weight kininogen, liberating bradykinin and terminating activation. In addition, the kallikrein formed on the surface of endothelial cells results in kinetically favorable activation of prourokinase and, subsequently, plasminogen. Activation of the plasma kallikrein/kinin system on endothelial cells proceeds by a physiological mechanism to initiate cellular fibrinolysis independent of plasmin, fibrin, and tissue-type plasminogen activator.

Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B 2 Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway

“…4 BK is produced locally through activation of the kallikrein-kinin system on the surface of endothelial cells. 17 BK is known to cause vasodilation through the B 2 receptor and subsequent effects on NO, prostacyclin, and EDHF production. 1 Data from the present study indicate that the effect of BK on endothelial tPA release is also mediated through activation of the B 2 subtype receptor but occurs through a NOS-and COX-independent pathway.…”

Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes

“…In the FXI activation assay, the cells were incubated with 10 nM HK, 5 nM FXI, and 20 nM FXII in binding buffer in the presence or absence of 100 M of peptides YHK9, FPF9, or IPP19 for 1 hour at 37°C. 16,22 At the end of the incubation, the cells were washed, 0.8 mM S2366 (DiaPharm) was added in HCB, and hydrolysis proceeded for an additional hour. The generated FXIa was quantified by measuring the absorbance of the reaction mixture at 405 nm.…”

“…11,15 In certain circumstances, FXII activation on endothelial cells is dependent upon prior PK activation. 15,16 Activated FXII increases the rate and extent of kallikrein formation on endothelial cells and initiates FXI activation in certain circumstances. 10,[15][16][17] FXII specifically binds to the endothelial cell membrane, and HK blocks FXII binding.…”

Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

“…They are hypotensive, increase vascular permeability, contract smooth muscle, and induce fever and pain. Although the best-understood mechanism for release of kinins is the plasma contact activation system involved in blood clotting, it has recently been shown that a CP on the surface of endothelial cells may be important in kinin release (Rojkjaer and Schmaier, 1999). Cathepsin X may potentiate bradykinin activity (see above).…”