Rat and human HARE/stabilin-2 are clearance receptors for high- and low-molecular-weight heparins

Authors

Ed Harris, University of Nebraska - LincolnFollow
Bruce A. Baggenstoss, University of Oklahoma Health Sciences Center
Paul H. Weigel, University of Oklahoma Health Sciences Center

Document Type

Article

Date of this Version

2009

Comments

Published in American Journal of Physiology - Gastrointestinal and Liver Physiology296 (2009), pp. 1191-1199; doi: 10.1152/ajpgi.90717.2008 Copyright 2009 American Physiological Society.
The APS does not permit archiving in an institutional repository, so the full-text article described here is linked from the APS journal site.

Abstract

The human hyaluronic acid (HA) receptor for endocytosis (HARE/ stabilin-2) is the primary clearance receptor for systemic HA, chondroitin sulfates, and heparin, but not for heparan sulfate or keratan sulfate (Harris EN, Weigel JA, Weigel PH. J Biol Chem 283: 17341– 17350, 2008). HARE is expressed in the sinusoidal endothelial cells (SECs) of liver and lymph nodes where it acts as a scavenger for uptake and degradation of glycosaminoglycans, both as free chains and proteoglycan fragments. Unfractionated heparin (UFH; ~14 kDa) and low-molecular-weight heparin (LMWH; ~4 kDa) are commonly used in treatments for thrombosis and cancer and in surgical and dialysis procedures. The reported half-lives of UFH and LMWH in the blood are ~1 h and 2–6 h, respectively. In this study, we demonstrate that anti-HARE antibodies specifically block the uptake of LMWH and UFH by isolated rat liver SECs and by human 293 cells expressing recombinant human HARE (hHARE). hHARE has a significant affinity (K_d = 10 μM) for LMWH, and higher affinity (K_d = 0.06 μM) for the larger UFH. Rat liver SECs or cells expressing the recombinant 190-kDa HARE isoform internalized both UFH and LMWH, and both heparins cross-compete with each other, suggesting that they share the same binding sites. These cellular results were confirmed in ELISA-like assays using purified soluble 190-hHARE ectodomain. We conclude that both UFH and LMWH are cleared by HARE/Stab2 and that the differences in the affinities of HARE binding to LMWH and UFH likely explain the longer in vivo circulating half-life of LMWH compared with UFH.