Reactive site-dependent phenotypic alterations in plasminogen activator inhibitor-1 transgenic mice.
BACKGROUND
Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators (PAs) and plays a role in the regulation of a number of physiological processes including the degradation of extracellular matrix proteins, cell proliferation and migration, and intracellular signaling.


OBJECTIVE
To characterize the effects of durable expression of a stable form of human PAI-1 and to characterize important structure-function relationships in PAI-1 in vivo.


METHODS
We developed transgenic mice lines overexpressing stable variants of human PAI-1 under the control of the murine preproendothelin-1 promoter and characterized the phenotypic alterations displayed by transgenic mice.


RESULTS
Transgenic mice expressing an active form of human PAI-1 (PAI-1-stab) display complex phenotypic abnormalities including alopecia and hepatosplenomegaly. Reactive site mutant transgenic mice expressing inactive PAI-1 exhibit complete phenotypic rescue, while transgenic mice expressing PAI-1 with reduced affinity for vitronectin manifest all of the phenotypic abnormalities present in PAI-1-stab transgenic mice.


CONCLUSIONS
The protease inhibitory activity of PAI-1 toward PAs and/or other serine proteases is necessary and sufficient to promote complex phenotypic abnormalities and mediates many of the physiological effects of PAI-1 in vivo.
Eren
M
M
Division of Cardiovascular Medicine, Department of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Gleaves
L A
LA
Atkinson
J B
JB
King
L E
LE
Declerck
P J
PJ
Vaughan
D E
DE
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
D017931:DNA Primers; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human