Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization.

P Carmeliet; L Kieckens; L Schoonjans; B Ream; A van Nuffelen; G Prendergast; M Cole; R Bronson; D Collen; R C Mulligan

doi:10.1172/JCI116892

Whitehead Institute for Biomedical Sciences, Cambridge, Massachusetts 02139-4307.

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Published in Volume 92, Issue 6 on December 1, 1993
J Clin Invest. 1993;92(6):2746–2755. https://doi.org/10.1172/JCI116892.
© 1993 The American Society for Clinical Investigation

Published December 1, 1993 - Version history

Homozygous plasminogen activator inhibitor-1 (PAI-1)-deficient (PAI-1-/-) mice were generated by homologous recombination in D3 embryonic stem cells. Deletion of the genomic sequences encompassing the transcription initiation site and the entire coding regions of murine PAI-1 was demonstrated by Southern blot analysis. A 3.0-kb PAI-1-specific mRNA was identified by Northern blot analysis in liver from PAI-1 wild type (PAI-1+/+) but not from PAI-1-/- mice. Plasma PAI-1 levels, measured 2-4 h after endotoxin (2.0 mg/kg) injection were 63 +/- 2 ng/ml, 30 +/- 10 ng/ml, and undetectable (< 2 ng/ml) in PAI-1+/+, heterozygous (PAI-1+/-) and PAI-1-/- mice, respectively (mean +/- SEM, n = 4-11). PAI-1-specific immunoreactivity was demonstrable in kidneys of PAI-1+/+ but not of PAI-1-/- mice. SDS-gel electrophoresis of plasma incubated with 125I-labeled recombinant human tissue-type plasminogen activator revealed an approximately 115,000-M(r) component with plasma from endotoxin-stimulated (0.5 mg/kg) PAI-1+/+ but not from PAI-1-/- mice, which could be precipitated with a polyclonal anti-PAI-1 antiserum. PAI-1-/- mice were viable, produced similar sizes of litters as PAI-1+/+ mice, and showed no apparent macroscopic or microscopic histological abnormalities.

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