Factor Xa-Evoked Relaxation in Rat Aorta: Involvement of PAR-2

Kawabata, Atsufumi; Kuroda, R.; Nakaya, Yumiko; Kawai, Kenzo; Nishikawa, Hiroyuki; Kawao, Naoyuki

doi:10.1006/bbrc.2001.4597

Cited by 47 publications

(33 citation statements)

References 28 publications

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“…Endogenous tryptase in mast cells and also coagulation factors VII and X in blood stream (40,41), novel candidates for endogenous PAR-2 activators, might become activated and/or accessible to PAR-2 present on the sensory neurons in the stomach during inflammation or tissue injury and trigger release of CGRP and tachykinins by activating PAR-2, resulting in secretion of mucus and mucosal protection. Trypsin that is now known to be expressed in a wide variety of tissues (13,42), including epithelial cells in the esophagogastrointestinal tract (42), could also be a candidate for endogenous activators of PAR-2 in the stomach, as described recently (34).…”

Section: Discussionmentioning

confidence: 99%

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Kawabata¹,

Kinoshita²,

Nishikawa³

et al. 2001

J. Clin. Invest.

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156

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Section: Discussionmentioning

confidence: 99%

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Kawabata¹,

Kinoshita²,

Nishikawa³

et al. 2001

J. Clin. Invest.

Self Cite

152

156

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“…Experimentally, PAR-2 may be activated by trypsin 25 (which may be extrapancreatic in origin 26 ), mast cell tryptase, 27 and coagulation factors VIIa 28 and Xa. 28,29 Moreover, the activator need not necessarily be endogenously derived, as evidenced by the recent demonstration of PAR-2 activation by a bacterial protease. 30 For the present experiments, we chose to activate PAR-2 using SLIGKV-NH 2 rather than a serine protease such as a trypsin.…”

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo

et al. 2003

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Background-Systemic hypotension as a consequence of vascular dysfunction is a well-recognized and important feature of critical illness. Although serine protease activation has been implicated as a cause of vascular dysfunction in systemic inflammation, the mechanism is unknown. Recently, a class of receptors with an entirely novel mechanism of action, protease-activated receptors (PARs), has been identified that would explain the link between protease activation and systemic hypotension. Our aim was to test the hypothesis that in vivo activation of protease-activated receptor 2 (PAR-2) in humans would mediate vasodilatation. Methods and Results-For these first-in-human studies, an activating peptide for the human PAR-2 receptor was synthesized and administered to healthy volunteers. Using both the dorsal hand vein technique and forearm plethysmography, we studied the effects of PAR-2 activation in human blood vessels and investigated the mechanism of vasodilation. Activation of PAR-2 receptors in vivo dilated human blood vessels in a dose-dependent manner, and the effects were reduced by inhibition of both nitric oxide and prostanoid synthesis Conclusions-These findings demonstrate that serine protease activity can cause human vasodilation and provide a possible explanation of why serine protease activation in critical illness is associated with vascular dysfunction.

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“…Indeed, Xa lacking a Gladomain is less potent than intact Xa for activating PAR2 (16), and Ruf and colleagues (17) have recently shown that TF/VIIa can promote PAR activation by serving as a Xa-binding site. EPR-1 has also been put forward as a Xa receptor or binding site (35,37), but its importance as such is unclear (19,38). Regardless, our data suggest that PARs are required for most if not all Xa signaling and that PAR knockout mice will provide a valuable strategy for defining the importance of Xa signaling in vivo.…”

Section: Par2 Is Expressed In Skin Endothelial Cells In Vivo-mentioning

confidence: 99%

“…Several pharmacological studies are consistent with this notion. For example, in HeLa cells, a PAR1-blocking antibody inhibited Xa-induced ERK phosphorylation and gene induction (18), and desensitization of PAR2 abolished Xa-induced relaxation of rat aortic rings (19). To further define the relative contribution of PARs to Xa signaling and to lay groundwork for studies to define the importance of Xa signaling in vivo, we utilized cells from PAR-deficient mice.…”

mentioning

confidence: 99%

Genetic Evidence That Protease-activated Receptors Mediate Factor Xa Signaling in Endothelial Cells

Camerer¹,

Kataoka²,

Kahn³

et al. 2002

Journal of Biological Chemistry

152

128

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The coagulation protease Factor Xa (Xa) 1 triggers a variety of cellular responses that may be important for inflammatory reactions to tissue injury. Protease-activated receptors (PAR1, PAR2, and PAR4) can mediate Xa signaling in heterologous expression systems. However, other candidate Xa receptors have been described, and the extent to which one or more PARs account for Xa signaling in relevant differentiated cells is unknown. We examined Xa signaling in endothelial cells from wildtype and PAR-deficient mice. Wild-type endothelial cells responded to agonists for PAR1, PAR2, and PAR4. Relative to wild-type, Xa-triggered phosphoinositide hydrolysis was reduced by 60 -75% in Par2 ؊/؊ endothelial cells, by 20 -30% in Par1 ؊/؊ endothelial cells, and by ϳ90% in Par2 ؊/؊ endothelial cells treated with a PAR1 antagonist. Similar results were obtained when ERK1/2 phosphorylation was used to assess Xa signaling. Thus PAR2 is the main endogenous Xa receptor in these endothelial cell preparations and, together, PAR2 and PAR1 appear to account for ϳ90% of endothelial Xa signaling. By contrast, in fibroblasts, PAR1 by itself accounted for virtually all Xa-induced phosphoinositide hydrolysis. This information is critical for the design and interpretation of knockout mouse studies to probe the possible roles of Xa signaling in vivo.The coagulation protease factor Xa (Xa) is generated at sites of vascular injury and inflammation by the actions of the tissue factor/VIIa (TF⅐VIIa) 1 and VIIIa⅐IXa complexes (1, 2). The formation of Xa is localized to the surfaces of cells and membrane vesicles, and in addition to binding Va to form the prothrombinase complex, Xa can directly regulate cellular behavior. For example, Xa can cause endothelial cells to release cytokines (3, 4), display adhesion molecules (4), proliferate (5), and trigger endothelial-dependent vasorelaxation (6). Importantly, studies in animal models of septic shock and the recent clinical trial of activated protein C strongly suggest that coagulation proteases contribute to organ damage and death in this syndrome (7)(8)(9)(10)(11)(12). Such studies have also raised the possibility that coagulation proteases upstream of thrombin might contribute to the pathogenesis of septic shock via activities unrelated to thrombin generation (11). These considerations motivate efforts to identify the receptors that mediate Xa responses in endothelial cells and other cell types.Protease-activated receptors (PARs) are G protein-coupled receptors that mediate signaling to thrombin and other proteases by a mechanism that requires proteolytic cleavage of the receptor (13). Because inhibitors that block the proteolytic activity of Xa also ablate its ability to trigger cellular responses, PARs are candidates for mediating Xa signaling (14,15). Indeed, there is substantial evidence that Xa can signal via PARs. For example, expression of PAR1, PAR2, and PAR4 in Xenopus oocytes confers calcium signaling in response to Xa (16). TF⅐VIIa complex can also activate PAR2 expressed in oocytes and...

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Factor Xa-Evoked Relaxation in Rat Aorta: Involvement of PAR-2

Cited by 47 publications

References 28 publications

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo

Genetic Evidence That Protease-activated Receptors Mediate Factor Xa Signaling in Endothelial Cells

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