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

Edward N. Harris, Bruce A. Baggenstoss, Paul H. Weigel

Research output: Contribution to journalArticle

28 Scopus citations

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 (Kd = 10 μM) for LMWH, and higher affinity (Kd = 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.

Original languageEnglish (US)
Pages (from-to)G1191-G1199
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number6
DOIs
StatePublished - Jun 1 2009

Keywords

  • Biotinylated heparin
  • Coated pit mediated
  • Endocytosis
  • Liver sinusoidal endothelial cells
  • Lovenox (enoxaparin)
  • Scavenger receptor

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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