Document Detail

Heparin selectively inhibits synthesis of tissue type plasminogen activator and matrix deposition of plasminogen activator inhibitor 1 by human mesangial cells.
MedLine Citation:
PMID:  7807964     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Mesangial changes in a variety of pathologic conditions involve mesangial cell proliferation and mesangial matrix remodelling. Heparin has been shown to prevent these processes in vivo. In vitro, heparin interferes with cell growth, proto-oncogene expression, synthesis of specific proteins, and extracellular matrix composition. In some cell types, it seems to interact with intracellular protein kinase C-dependent pathways. The effect of heparin on the mesangial plasminogen activating system (tissue type plasminogen activator, t-PA, and plasminogen activator inhibitor type 1, PAI-1), which is thought to be involved in matrix remodelling, has not been previously reported. EXPERIMENTAL DESIGN: Cultured human mesangial cells were stimulated by 10% fetal calf serum (FCS) or 16 nM phorbol myristate acetate (PMA) in the presence or absence of anticoagulant or nonanticoagulant heparins. Cell proliferation, synthesis of t-PA and PAI-1, cell morphology, and PAI-1 matrix deposition were studied using cell counting, [3H]thymidine incorporation, specific t-PA and PAI-1 enzyme-linked immunosorbent assay, Northern blot analysis, light microscopy, immunofluorescence and immunogold silver staining with combined bright-field and epipolarization microscopy. RESULTS: Heparin partially inhibited FCS-stimulated cell growth but not PMA-induced thymidine incorporation. FCS and PMA stimulated t-PA (p < 0.05 and p < 0.01, respectively) and PAI-1 synthesis (p < 0.05 and p < 0.01 respectively). Heparin selectively and partially inhibited FCS-stimulated t-PA, but not PAI-1 synthesis. It has no effect on PMA-stimulated t-PA or PAI-1 synthesis but prevented cell shape-changes induced by PMA, suggesting that heparin inhibits some but not all protein kinase C (PKC)-dependent effects and that heparin block in t-PA synthesis is distal to PKC activation. Heparin decreased PAI-1 matrix accumulation. Similar distal to PKC activation. Heparin decreased PAI-1 matrix accumulation. Similar results were observed with anticoagulant and nonanticoagulant heparin fragments. CONCLUSIONS: In human mesangial cells, anticoagulant and nonanticoagulant heparin exert an antiproliferative effect and may prevent mesangial matrix changes by decreasing FCS-stimulated t-PA synthesis and PAI-1 deposition in the matrix. Heparin is able to inhibit PKC-dependent cell shape changes but not PKC-dependent t-PA or PAI-1 synthesis. It also inhibits PKC-independent cell proliferation and t-PA synthesis. These results suggest multiple intracellular sites of action for heparin, unrelated or distal to PKC activation.
J Hagège; F Delarue; M N Peraldi; J D Sraer; E Rondeau
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Laboratory investigation; a journal of technical methods and pathology     Volume:  71     ISSN:  0023-6837     ISO Abbreviation:  Lab. Invest.     Publication Date:  1994 Dec 
Date Detail:
Created Date:  1995-01-27     Completed Date:  1995-01-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376617     Medline TA:  Lab Invest     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  828-37     Citation Subset:  IM    
Inserm U 64 and Association Claude Bernard, Hôpital Tenon, Paris, France.
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MeSH Terms
Blotting, Northern
Cell Division / drug effects
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Glomerular Mesangium / cytology,  drug effects*
Heparin / chemistry,  pharmacology*
Heparitin Sulfate / pharmacology
Microscopy, Polarization
Plasminogen Activator Inhibitor 1 / biosynthesis*,  immunology
Tetradecanoylphorbol Acetate / pharmacology
Tissue Plasminogen Activator / biosynthesis*
Reg. No./Substance:
0/Plasminogen Activator Inhibitor 1; 16561-29-8/Tetradecanoylphorbol Acetate; 9005-49-6/Heparin; 9050-30-0/Heparitin Sulfate; EC Plasminogen Activator

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