Heparin potentiates the action of acidic fibroblast growth factor by prolonging its biological half-life.
The mechanism(s) by which heparin influences the biological activities of acidic and basic fibroblast growth factors (aFGF and bFGF) is not completely understood. One mechanism by which heparin could alter the biological activities of aFGF and bFGF is by altering their biological half-lives. We investigated the possibility that heparin potentiates aFGF-induced neurite outgrowth from PC12 cells by prolonging its biological half-life. Under conditions where heparin potentiated aFGF-induced neurite outgrowth, we observed that heparin increased the biological half-life of aFGF from 7 to 39 hr. We determined that greater than 25 hr of exposure to active aFGF was required for induction of neurite outgrowth. If aFGF activity was maintained for greater than 25 hr by periodic readdition of factor, heparin no longer potentiated aFGF-induced neurite outgrowth. These observations strongly suggest that heparin potentiates the activity of aFGF by prolonging its biological half-life. The protease inhibitors hirudin, leupeptin, and pepstatin A did not potentiate aFGF-induced neurite outgrowth, indicating that proteases inhibited by these inhibitors are not responsible for the loss of aFGF activity that we observed. However, aprotinin potentiated aFGF neurite-promoting activity approximately sevenfold, indicating that proteases that are inhibited by aprotinin are at least partially responsible for aFGF inactivation. These observations suggest that heparin regulates the activity of aFGF by regulating its proteolytic degradation, thereby regulating its biological half-life.
Damon
D H
DH
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
Lobb
R R
RR
D'Amore
P A
PA
Wagner
J A
JA
D000310:Adrenal Gland Neoplasms / Q000473:pathology; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D001369:Axons / Q000187:drug effects* / Q000648:ultrastructure; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D005346:Fibroblast Growth Factors / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006493:Heparin / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism; D010673:Pheochromocytoma / Q000473:pathology; D051381:Rats; D013917:Thrombin / Q000494:pharmacology
D005346:Fibroblast Growth Factors; D006493:Heparin; D007611:Aprotinin; D010447:Peptide Hydrolases; D013917:Thrombin