Differential Expression of Functional Protease-Activated Receptor-2 (PAR-2) in Human Vascular Smooth Muscle Cells

Molino, Marina; Raghunath, Puthiyaveettil N.; Kuo, Alice; Ahuja, Menaka; Hoxie, James A.; Brass, Lawrence F.; Barnathan, Elliot S.

doi:10.1161/01.atv.18.5.825

Cited by 59 publications

(45 citation statements)

References 38 publications

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“…Notwithstanding the experimental evidence that PAR-2, expressed in endothelial cells 60 and vascular smooth muscle cells, 61 is efficiently activated by Xa, 20,62 endogenously expressed PAR-1 is here clearly shown to be a target for activation by Xa in a tumor cell line. The Xa-dependent activation of PAR-1 suggests that Xa may function as a more generalized proteolytic signal by bypassing the restricted expression of members of the PAR family in certain vascular (eg, monocytes/macrophages) and extravascular (eg, tumor cells) cell types that frequently stain positively for Xa.…”

Section: Discussionmentioning

confidence: 66%

Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1

Riewald

Kravchenko

Petrovan

et al. 2001

Blood

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179

142

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Section: Discussionmentioning

confidence: 66%

Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1

Riewald

Kravchenko

Petrovan

et al. 2001

Blood

Self Cite

179

142

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“…PAR-2 is widely expressed by vascular endothelial (42)(43)(44) and smooth muscle cells (45,46), and is thought to play a role in the regulation of BP and vascular tone (47). It belongs to the family of G protein-coupled receptors activated by limited proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-β, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-β gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-β expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN. E-mail: g.grandaliano@nephro.uniba.it

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“…In order to provide further evidence for PAR-2 expression, indirect immunofluorescence studies were carried out on some human (Molino et al, 1998), studies were carried out on non-permeabilized cells. First, we investigated two cell lines exhibiting expression of PAR-2 mRNA in Northern blotting experiments, i.e.…”

Section: Expression Of Par-2 Receptor By Human Colon Cancer Cell Linesmentioning

confidence: 99%

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

et al. 2001

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SummaryThe protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. We investigated the expression of PAR-2 and the role of trypsin in cell proliferation in human colon cancer cell lines. A total of 10 cell lines were tested for expression of PAR-2 mRNA by Northern blot and RT-PCR. PAR-2 protein was detected by immunofluorescence. Trypsin and the peptide agonist SLIGKV (AP2) were tested for their ability to induce calcium mobilization and to promote cell proliferation on serum-deprived cells. PAR-2 mRNA was detected by Northern blot analysis in 6 out of 10 cell lines Cl.19A, SW480,. Other cell lines expressed low levels of transcripts, which were detected only by RT-PCR. Further results were obtained with HT-29 cells: (1) PAR-2 protein is expressed at the cell surface; (2) an increase in intracellular calcium concentration was observed upon trypsin (1-100 nM) or AP2 (10-100 µM) challenges; (3) cells grown in serum-deprived media supplemented with trypsin (0.1-1 nM) or AP2 (1-300 µM) exhibited important mitogenic responses (3-fold increase of cell number). Proliferative effects of trypsin or AP2 were also observed in other cell lines expressing PAR-2. These data show that subnanomolar concentrations of trypsin, acting at PAR-2, promoted the proliferation of human colon cancer cells. The results of this study indicate that trypsin could be considered as a growth factor and unravel a new mechanism whereby serine proteases control colon tumours.

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Differential Expression of Functional Protease-Activated Receptor-2 (PAR-2) in Human Vascular Smooth Muscle Cells

Cited by 59 publications

References 38 publications

Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1

Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

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