Activated Protein C Directly Activates Human Endothelial Gelatinase A

Nguyen, Minh Vu Chuong; Arkell, Jacky; Jackson, Chris

doi:10.1074/jbc.275.13.9095

Cited by 100 publications

(68 citation statements)

References 22 publications

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“…APC stimulated the expression and activation of MMP-2 in RA fibroblasts and Mac6 cells, which is consistent with the previous findings using endothelial cells, normal fibroblasts, and keratinocytes (40,41). Interestingly, in RA monocytes, which do not normally produce MMP-2, APC is unable to induce this enzyme.…”

Section: Discussionsupporting

confidence: 91%

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

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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.

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Section: Discussionsupporting

confidence: 91%

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

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“…Using zymogen PC, chemically inactivated DEGR-APC, and an active site mutant of APC (S195A) with the MDA-MB-231 cancer cells, one finding of our study showed that the active protease was needed to increase cell migration. Therefore, unlike the inhibitory role of APC with lymphocytes, the pro-migratory role of APC in the MDA-MB-231 cells requires the active site of the protease, most likely to bind and activate receptors, such as PAR-1 [20,21,26,30,31], and to activate extracellular matrix proteases, such as MMP-2 and MMP-9 [27,46,47]. It is possible that when bound to EPCR, APC may undergo modifications to its macromolecular substrate recognition.…”

Section: Discussionmentioning

confidence: 99%

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Beaulieu

Church

2007

Experimental Cell Research

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Activated protein C (APC) is a serine protease that regulates thrombin (IIa) production through inactivation of blood coagulation factors Va and VIIIa. APC also has non-hemostatic functions related to inflammation, proliferation, and apoptosis through various mechanisms. Using two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, we investigated the role of APC in cell chemotaxis and invasion. Treatment of cells with increasing APC concentrations (1-50 μg/ml) increased invasion and chemotaxis in a concentration-dependent manner. Only the active form of APC increased invasion and chemotaxis of the MDA-MB-231 cells when compared to 3 inactive APC derivatives. Using a modified "checkerboard" analysis, APC was shown to only affect migration when plated with the cells; therefore, APC is not a chemoattractant. Blocking antibodies to endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) attenuated the effects of APC on chemotaxis in the MDA-MB-231 cells. Finally, treatment of the MDA-MB-231 cells with the proliferation inhibitor, Na butyrate, showed that APC did not increase migration by increasing cell number. Therefore, APC increases invasion and chemotaxis of cells by binding to the cell surface and activating specific signaling pathways through EPCR and PAR-1.

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“…However, our findings concerning MMP concentrations are not consistent with some other studies, which have themselves shown conflicting results [23,24], demonstrating different concentrations of MMPs. As MMP-2 is predominantly secreted by endothelial cells and MMP-9 is the major MMP secreted from macrophages [13][14]19], their concentrations might be expected to change with the development of vascular complications in diabetic patients. Most of the diabetic patients enrolled in this study, however, had been diagnosed within the 3 preceding years and consequently had mild, if any, diabetic complications.…”

Section: Discussionmentioning

confidence: 99%

“…The major MMP species expressed in the vasculature include MMP-1, MMP-2 (72-kDa gelatinase A), MMP-3, MMP-9 (92-kDa gelatinase B), and membrane type (MT) 1-MMP. MMP-1, MMP-2, and MMP-3 are predominantly secreted by endothelial cells [13], while the major MMP secreted from macrophages is MMP-9 [14]. The gelatinases readily digest denatured collagens and gelatins.…”

Section: Introductionmentioning

confidence: 99%

Alterations in peripheral blood levels of TIMP-1, MMP-2, and MMP-9 in patients with type-2 diabetes

Lee

Song

Shin

et al. 2005

Diabetes Research and Clinical Practice

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Activated Protein C Directly Activates Human Endothelial Gelatinase A

Cited by 100 publications

References 22 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

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Alterations in peripheral blood levels of TIMP-1, MMP-2, and MMP-9 in patients with type-2 diabetes

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