Protection of transforming growth factor-beta 1 activity by heparin and fucoidan.
The transforming growth factor-beta (TGF-beta) family of proteins exert diverse and potent effects on proliferation, differentiation, and extracellular matrix synthesis. However, relatively little is known about the stability or processing of endogenous TGF-beta activity in vitro or in vivo. Our previous work indicated that 1) TGF-beta 1 has strong heparin-binding properties that were not previously recognized because of neutralization by iodination, and 2) heparin, and certain other polyanions, could block the binding of TGF-beta 1 to alpha 2-macroglobulin (alpha 2-M). The present studies investigated the influence of heparin-like molecules on the stability of the TGF-beta 1 signal in the pericellular environment. The results indicate that heparin and fucoidan, a naturally occurring sulfated L-fucose polymer, suppress the formation of an initial non-covalent interaction between 125I-TGF-beta 1 and activated alpha 2-M. Electrophoresis of 125I-TGF-beta 1 showed that fucoidan protects TGF-beta 1 from proteolytic degradation by plasmin and trypsin. While plasmin caused little, if any, activation of latent TGF-beta derived from vascular smooth muscle cells (SMC), plasmin degraded acid-activated TGF-beta, and purified TGF-beta 1, and this degradation was inhibited by fucoidan. In vitro, heparin and fucoidan tripled the half-life of 125I-TGF-beta 1 and doubled the amount of cell-associated 125I-TGF-beta 1. Consistent with this protective effect, heparin- and fucoidan-treated SMC demonstrated elevated levels of active, but not latent, TGF-beta activity.
McCaffrey
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Department of Medicine, Cornell University Medical College, New York, New York 10021.
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Vicente
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Consigli
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Borth
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D000818:Animals; D000838:Anions / Q000494:pharmacology; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D005341:Fibrinolysin / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D014357:Trypsin / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000378:metabolism
D000838:Anions; D000925:Anticoagulants; D007457:Iodine Radioisotopes; D011134:Polysaccharides; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins; D006493:Heparin; C007789:fucoidan; D014357:Trypsin; D005341:Fibrinolysin