Gene targeting in hemostasis. Alpha2-antiplasmin.
Apha2-antiplasmin (AP), the main physiological plasmin inhibitor in mammalian plasma, is a 70 kDa single chain serpin (serine proteinase inhibitor) with reactive site peptide bond Arg-Met. It inhibits plasmin very rapidly (second-order inhibition rate constant of = 2 x 107 M-1.s-1) following formation of an inactive 1:1 stoichiometric complex. The high reaction rate requires the presence of a free active site and free lysine-binding site(s) in plasmin. The pathophysiologic relevance of AP is suggested by the finding that homozygous deficient patients show a bleeding tendency; heterozygotes, in contrast, frequently have no or only mild bleeding complications. Inactivation of the AP gene in mice was achieved by replacing, via homologous recombination in embryonic stem cells, a 7 kb genomic sequence encoding the entire murine protein with the neomycin resistance expression cassette. Homozygous AP deficient mice display normal fertility, viability and development. They have an enhanced endogenous fibrinolytic capacity without overt bleeding; this is reflected by a higher spontaneous lysis rate of experimental pulmonary emboli, by a reduced fibrin deposition in the kidneys following challenge with endotoxin, by more limited photochemically induced arterial thrombosis, and by reduced infarct size following induction of focal cerebral ischemia by ligation of the left middle cerebral artery. In a vascular injury restenosis model, AP deficiency has no significant effect on smooth muscle cell migration and neointima formation. These data suggest that, at least in the murine system, the main role of alpha2-antiplasmin is in regulating plasmin activity in the circulating blood and in controlling intravascular fibrinolysis.
Lijnen
H R
HR
Center for Molecular and Vascular Biology, University of Leuven, Campus, Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. roger.lijnen@med.kuleuven.ac.be
D000818:Animals; D002318:Cardiovascular Diseases / Q000503:physiopathology; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology; D018390:Gene Targeting; D018095:Germ-Line Mutation; D006487:Hemostasis / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D010641:Phenotype; D020521:Stroke / Q000503:physiopathology; D000979:alpha-2-Antiplasmin / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D000979:alpha-2-Antiplasmin; D005341:Fibrinolysin