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 language | English (US) |
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Pages (from-to) | 21117-21122 |
Number of pages | 6 |
Journal | Journal of Biological Chemistry |
Volume | 269 |
Issue number | 33 |
State | Published - Aug 19 1994 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology