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J Biol Chem, Vol. 274, Issue 53, 37685-37692, December 31, 1999

Role of the Low Density Lipoprotein-related Protein Receptor in Mediation of Factor VIII Catabolism*

Evgueni L. SaenkoDagger , Alexey V. Yakhyaev, Irina Mikhailenko, Dudley K. Strickland, and Andrei G. Sarafanov

From the Holland Laboratory, American Red Cross, Rockville, Maryland 20855

In the present study, we found that catabolism of coagulation factor VIII (fVIII) is mediated by the low density lipoprotein receptor-related protein (LPR), a liver multiligand endocytic receptor. In a solid phase assay, fVIII was shown to bind to LRP (Kd 116 nM). The specificity was confirmed by a complete inhibition of fVIII/LRP binding by 39-kDa receptor-associated protein (RAP), an antagonist of all LRP ligands. The region of fVIII involved in its binding to LRP was localized within the A2 domain residues 484-509, based on the ability of the isolated A2 domain and the synthetic A2 domain peptide 484-509 to prevent fVIII interaction with LRP. Since vWf did not inhibit fVIII binding to LRP, we proposed that LRP receptor may internalize fVIII from its complex with vWf. Consistent with this hypothesis, mouse embryonic fibroblasts that express LRP, but not fibroblasts genetically deficient in LRP, were able to catabolize 125I-fVIII complexed with vWf, which was not internalized by the cells. These processes could be inhibited by RAP and A2 subunit of fVIII, indicating that cellular internalization and degradation were mediated by interaction of the A2 domain of fVIII with LRP. In vivo studies of 125I-fVIII·vWf complex clearance in mice demonstrated that RAP completely inhibited the fast phase of the biphasic 125I-fVIII clearance that is responsible for removal of 60% of fVIII from circulation. Inhibition of the RAP-sensitive phase prolonged the half-life of 125I-fVIII in circulation by 3.3-fold, indicating that LRP receptor plays an important role in fVIII clearance.

* This work was supported in part by National Institutes of Health Grant HL50784 (to D. K. S) and by Scientist Development Grant 9630065N (to E. L. S.) from the American Heart Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. Tel.: 301-738-0743; Fax: 301-738-0794.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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