Activation of Endothelial Cell Protease Activated Receptor 1 by the Protein C Pathway

Riewald, Matthias; Petrovan, Ramona J.; Donner, Aaron J; Mueller, Barbara M.; Ruf, Wolfram

doi:10.1126/science.1071699

Cited by 791 publications

(800 citation statements)

References 24 publications

Supporting

Mentioning

763

Contrasting

Unclassified

Order By: Relevance

“…EPCR is not known to be a signaling receptor, so the intracellular signaling mechanism for the inhibition of NF-B is unknown. It is possible that by binding to EPCR, APC promotes the activation of protease-activated receptors (PARs), in particular PAR-1, which contributes to the antiinflammatory actions of APC (43).…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Xue

March

Sambrook

2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To investigate the in vitro effect of activated protein C (APC), a natural anticoagulant and novel antiinflammatory agent, on the regulation of the gelatinases matrix metalloproteinase 2 (MMP-2) and MMP-9.Methods. Synovial fibroblasts and peripheral blood monocytes isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and Mono Mac6 cells were used in this study. After treatment, cells and culture supernatants were collected for zymography, enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and Western blot analysis.Results. Fibroblasts and monocytes from RA patients produced substantially more MMP-9 than did those from OA patients; however, there was no difference in MMP-2 production. The addition of recombinant APC markedly reduced MMP-9 at the gene and protein levels. In contrast, APC up-regulated and activated MMP-2. Using a blocking antibody to the endothelial protein C receptor (EPCR), we showed that the inhibition of MMP-9 by APC was EPCR-dependent. Furthermore, APC directly suppressed the production of tumor necrosis factor (TNF) and the activation of NF-B and MAP kinase p38, and inhibitors of NF-B or p38 reduced the production of MMP-9, suggesting that APC inhibits MMP-9 by blocking TNF, NF-B, and p38. Thus, APC acts on MMP-9 by binding to EPCRs on the cell surface and, subsequently, inhibiting the intracellular activation of the proinflammatory signaling molecules NF-B and p38.Conclusion. APC appears to be the first physiologic agent to inhibit the production of proinflammatory MMP-9, yet increase antiinflammatory MMP-2 activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Xue

March

Sambrook

2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…Notably, in adult animals, PAR1 is expressed at moderate to high levels in brain regions involved with emotional learning, including hippocampus and amygdala (Striggow et al, 2001). PAR1 has been extensively studied for its role in coagulation and hemostasis (Coughlin, 2000;Macfarlane et al, 2001), as well as in the survival of neurons following ischemic, traumatic, or neurotoxic insults (Gingrich & Traynelis, 2000a;Shibata et al, 2001;Riewald et al, 2002;Suo et al, 2002;Cheng et al, 2003;Junge et al, 2003;Xi et al, 2003;Guo et al, 2004;Olson et al, 2004;Hamill et al, 2005;Nicole et al, 2005). Surprisingly little, however, is known about PAR1's roles in normal brain function.…”

Section: Introductionmentioning

confidence: 99%

Learning and memory deficits in mice lacking protease activated receptor-1

Almonte

Hamill

Chhatwal

et al. 2007

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally-motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1−/− animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally-motivated learning.

show abstract

“…PAR1, the prototypic receptor of the family, is activated via a spectrum of serine proteases taking part in the thrombotic/hemostasis cascade, including thrombin (3), plasmin (4), Xa (5), and activated protein C (6). Human Par1 (hPar1) plays a distinct role in the progression of malignant epithelia as well as in the physiologic invasion process of trophoblast implantation in the uterus decidua (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Salah

Maoz

Pokroy

et al. 2007

Molecular Cancer Research

View full text Add to dashboard Cite

Although ample evidence point to the central involvement of protease activated receptor-1 (PAR1) in tumor progression, little is known about the fate of the tumor when hPar1 is being silenced. We observed that hPar1 antisense clones exhibit low PAR1 levels, attenuated cell proliferation and invasion in vitro, and tumor formation in vivo. These clones showed noticeably reduced paxillin phosphorylation compared with the parental A375SM cells, whereas no change in the integrin levels was noticed. Antisense clones injected into the mice resulted in very few and only occasional small tumors, whereas advanced and vascularized tumors were observed in A375SM cells. The antisense-derived tumor sections expressed active caspase-3, increased terminal deoxynucleotidyl transferase -mediated nick-end labeling staining, and a markedly reduced proliferating cell nuclear antigen level compared with A375SM cell -derived tissue sections. Likewise, ablation of the hPar1 gene in a tetracyclineinducible hPar1 system leads to apoptosis in immature blood vessels, whereas mature vessels were unaffected. The activation of PAR1-induced pAkt/protein kinase B abrogated serum-deprived Bim EL induction and also markedly inhibited Bax levels. On the other hand, small interfering RNA silencing of the hPar1 gene induced the expression of Bim EL , a direct substrate of Akt/protein kinase B and also induced expression of active caspase-9 and caspase-3. These results altogether identify PAR1 as a survival factor that protects cells from undergoing apoptosis. We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation. (Mol Cancer Res 2007;5(3):229 -40)

show abstract

Activation of Endothelial Cell Protease Activated Receptor 1 by the Protein C Pathway

Cited by 791 publications

References 24 publications

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

Learning and memory deficits in mice lacking protease activated receptor-1

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Contact Info

Product

Resources

About