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http://purl.uniprot.org/citations/22479366http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22479366http://www.w3.org/2000/01/rdf-schema#comment"

Objective

Granzyme B (GrB) is a pro-apoptotic serine protease that contributes to immune-mediated target cell apoptosis. However, during inflammation, GrB accumulates in the extracellular space, retains its activity, and is capable of cleaving extracellular matrix (ECM) proteins. Recent studies have implicated a pathogenic extracellular role for GrB in cardiovascular disease, yet the pathophysiological consequences of extracellular GrB activity remain largely unknown. The objective of this study was to identify proteoglycan (PG) substrates of GrB and examine the ability of GrB to release PG-sequestered TGF-β1 into the extracellular milieu.

Methods/results

Three extracellular GrB PG substrates were identified; decorin, biglycan and betaglycan. As all of these PGs sequester active TGF-β1, cytokine release assays were conducted to establish if GrB-mediated PG cleavage induced TGF-β1 release. Our data confirmed that GrB liberated TGF-β1 from all three substrates as well as from endogenous ECM and this process was inhibited by the GrB inhibitor 3,4-dichloroisocoumarin. The released TGF-β1 retained its activity as indicated by the induction of SMAD-3 phosphorylation in human coronary artery smooth muscle cells.

Conclusion

In addition to contributing to ECM degradation and the loss of tissue structural integrity in vivo, increased extracellular GrB activity is also capable of inducing the release of active TGF-β1 from PGs."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.org/dc/terms/identifier"doi:10.1371/journal.pone.0033163"xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/author"Zhao H."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/author"Boivin W.A."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/author"Granville D.J."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/author"Shackleford M."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/author"Knight D.A."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/author"Hackett T.L."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/author"Vanden Hoek A."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/name"PLoS One"xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/pages"e33163"xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/title"Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-beta1."xsd:string
http://purl.uniprot.org/citations/22479366http://purl.uniprot.org/core/volume"7"xsd:string
http://purl.uniprot.org/citations/22479366http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/22479366
http://purl.uniprot.org/citations/22479366http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/22479366
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http://purl.uniprot.org/uniprot/#_A0A078BCH8-mappedCitation-22479366http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/22479366
http://purl.uniprot.org/uniprot/#_A0A078BFK3-mappedCitation-22479366http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/22479366
http://purl.uniprot.org/uniprot/#_A0A0S2Z3J8-mappedCitation-22479366http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/22479366
http://purl.uniprot.org/uniprot/#_A0A0S2Z3L3-mappedCitation-22479366http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/22479366
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