Enhanced fibrinolytic potential in mice with combined homozygous deficiency of alpha2-antiplasmin and PAI-1.
Alpha2-antiplasmin (alpha2-AP) and plasminogen activator inhibitor-1 (PAI-1) are the main physiological inhibitors of the plasminogen/plasmin system in mammalian plasma. In the present study, the relative importance of both inhibitors was evaluated with the use of mice with single or combined deficiency of alpha2-AP and PAI-1 in the same genetic background. Mice with combined deficiency (alpha2-AP-/-:PAI-1-/-) are viable, develop normally and are fertile. After amputation of the tail, bleeding times are prolonged (>15 min) in alpha2-AP-/-: PAI-1-/- mice, as compared to double wild-type or single deficient mice (4.6 to 10 min). Spontaneous lysis after 4 h of intravenously injected 125I-fibrin labeled plasma clots is significantly higher in mice with alpha2-AP deficiency both in the PAI-1+/+ background (89+/-2% versus 42+/-3%; p = 0.002) and in the PAI-1-/- background (83+/-4% versus 53+/-5%; p = 0.002). PAI-1 deletion in the alpha2-AP+/+ or alpha2-AP-/- background, however, has no significant effect (p = 0.13 or 0.18, respectively). Four hours after endotoxin injection, fibrin deposition in the kidneys is not significantly affected by PAI-1 deletion in mice with alpha2-AP+/+ or alpha2-AP-/- background (p = 0.07 and 0.19, respectively). In contrast, alpha2-AP deletion causes significantly reduced fibrin deposition in the PAI-1+/+ background (p = 0.01). Endotoxin injection causes a dramatic increase in PAI-1 antigen levels in kidney extracts of PAI-1+/+ animals, without effect on alpha2-AP levels. Taken together, these data indicate that the higher endogenous fibrinolytic capacity observed in mice with combined deficiency is mainly due to the lack of alpha2-AP and suggest a less important role for PAI-1.
Dewerchin
M
M
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium. mieke.dewerchin@med.kuleuven.ac.be
Collen
D
D
Lijnen
H R
HR
D000818:Animals; D001760:Bleeding Time; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism; D005342:Fibrinolysis; D005838:Genotype; D006720:Homozygote; D007150:Immunohistochemistry; D007668:Kidney / Q000737:chemistry; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000502:physiology*; D000979:alpha-2-Antiplasmin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D004731:Endotoxins; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D000979:alpha-2-Antiplasmin; D005337:Fibrin