Low density lipoprotein receptor-related protein is necessary for the internalization of both tissue-type plasminogen activator-inhibitor complexes and free tissue-type plasminogen activator

Kim Orth, Thomas Willnow, Joachim Herz, Mary Jane Gething, Joseph Sambrook

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Abstract

Tissue-type plasminogen activator (t-PA) is used as a thrombolytic agent in treatment of myocardial infarction. However, large doses of this agent must be administered in treatment to maintain a thrombolytic state because t- PA is cleared rapidly from circulation. We designed specific ligands to distinguish between two major mechanisms by which t-PA is taken into cells and degraded. One of these mechanisms involves internalization of complexes between t-PA and its cognate inhibitor plasminogen activator inhibitor type- 1 (PAI-1); the other mechanism is independent of PAI-1. Using specific inhibitors for low density lipoprotein receptor-related protein/α2- macroglobulin receptor (LRP), we show that the degradation by hepatocytes of both free t-PA and t-PA·PAI-1 complexes involve the receptor LRP. We demonstrate that fibroblasts degrade both free t-PA (PAI-1-independent) and t-PA complexed with its specific inhibitor PAI-1 (PAI-1-dependent), whereas genetically altered fibroblasts that do not express LRP neither internalize nor degrade these ligands. We also show that a PAI-1-independent, t-PA ligand can inhibit the degradation of both free t-PA and t-PA·PAI-1 complexes. We propose LRP is the receptor for both PAI-1-independent and PAI-1-dependent t- PA ligands.

Original languageEnglish (US)
Pages (from-to)21117-21122
Number of pages6
JournalJournal of Biological Chemistry
Volume269
Issue number33
Publication statusPublished - Aug 19 1994

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ASJC Scopus subject areas

  • Biochemistry

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