| Caspase-3-mediated secretion of connective tissue growth factor by apoptotic endothelial cells promotes fibrosis. | |
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MedLine Citation:
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PMID: 19730442 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apoptosis of endothelial cells (ECs) is an early pathogenic event in various fibrotic diseases. In this study, we evaluated whether paracrine mediators produced by apoptotic ECs play direct roles in fibrogenesis. C3H mice injected subcutaneously with serum-free medium conditioned by apoptotic ECs (SSC) showed increased skin thickness and heightened protein levels of alpha-smooth-muscle actin (alphaSMA), vimentin and collagen I as compared with mice injected with medium conditioned by non-apoptotic ECs. Fibroblasts exposed to SSC in vitro showed cardinal features of myofibroblast differentiation with increased stress fiber formation and expression of alphaSMA. Caspase-3 silencing in ECs prevented the release of mediators favoring myofibroblast differentiation. To identify the fibrogenic factor(s) released by ECs, the protein contents of media conditioned by either apoptotic or non-apoptotic ECs were compared using SDS-PAGE-liquid chromatography (LC)-tandem mass spectrometry (MS/MS) and two-dimensional LC-MS/MS. Connective tissue growth factor (CTGF) was the only fibrogenic protein found increased in SSC. Pan-caspase inhibition with ZVAD-FMK or caspase-3 silencing in ECs confirmed that CTGF was released downstream of caspase-3 activation. The fibrogenic signaling signatures of SSC and CTGF on fibroblasts in vitro were similarly Pyk2-, Src-family kinases- and PI3K dependent, but TGF-beta-independent. CTGF-immunodepleted SSC failed to induce myofibroblast differentiation in vitro and skin fibrosis in vivo. These results identify caspase-3 activation in ECs as a novel inducer of CTGF release and fibrogenesis. |
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Authors:
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P Laplante; I Sirois; M-A Raymond; V Kokta; A Béliveau; A Prat; A V Pshezhetsky; M-J Hébert |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-09-04 |
Journal Detail:
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Title: Cell death and differentiation Volume: 17 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-11 Completed Date: 2010-07-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 291-303 Citation Subset: IM |
Affiliation:
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CRCHUM (Centre de Recherche du Centre Hospitalier de l'Université de Montréal)-Hôpital Notre-Dame and Université de Montréal, Montreal, QC, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / physiology Caspase 3 / metabolism* Cell Differentiation / physiology Connective Tissue Growth Factor / metabolism*, secretion Disease Models, Animal Endothelial Cells / cytology Female Fibroblasts / cytology Fibrosis Humans Mice Mice, Inbred C3H Paracrine Communication / physiology Signal Transduction / physiology Skin Diseases / metabolism*, pathology* Umbilical Veins / cytology |
| Grant Support | |
ID/Acronym/Agency:
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MOP-66980//Canadian Institutes of Health Research; MOP-89869//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/CTGF protein, human; 0/Ctgf protein, mouse; 139568-91-5/Connective Tissue Growth Factor; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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