title: Role of plasminogen system components in focal cerebral ischemic infarction: a gene targeting and gene transfer study in mice.
abstract: BACKGROUND
  The role of plasminogen system components in focal cerebral ischemic infarction (FCI) was studied in mice deficient in plasminogen (Plg-/-), in tissue or urokinase plasminogen activator (tPA-/- or uPA-/-), or in plasminogen activator inhibitor-1 or alpha2-antiplasmin (PAI-1(-/-) or alpha2-AP-/-).
  
  
  RESULTS
  FCI was produced by ligation of the left middle cerebral artery and measured after 24 hours by planimetry of stained brain slices. In control (wild-type) mice, infarct size was 7.6+/-1.1 mm3 (mean+/-SEM), uPA-/- mice had similar infarcts (7.8+/-1.0 mm3, P=NS), tPA-/- mice smaller (2.6+/-0.80 mm3, P<0.0001), PAI-1(-/-) mice larger (16+/-0.52 mm3, P<0.0001), and Plg-/- mice larger (12+/-1.2 mm3, P=0.037) infarcts. alpha2-AP-/- mice had smaller infarcts (2. 2+/-1.1 mm3, P<0.0001 versus wild-type), which increased to 13+/-2.5 mm3 (P<0.005 versus alpha2-AP-/-) after intravenous injection of human alpha2-AP. Injection into alpha2-AP-/- mice of Fab fragments of affinospecific rabbit IgG against human alpha2-AP, after injection of 200 microg human alpha2-AP, reduced FCI from 11+/-1.5 to 5.1+/-1.1 mm3 (P=0.004).
  
  
  CONCLUSIONS
  Plg system components affect FCI at 2 different levels: (1) reduction of tPA activity (tPA gene inactivation) reduces whereas its augmentation (PAI-1 gene inactivation) increases infarct size, and (2) reduction of Plg activity (Plg gene inactivation or alpha2-AP injection) increases whereas its augmentation (alpha2-AP gene inactivation or alpha2-AP neutralization) reduces infarct size. Inhibition of alpha2-AP may constitute a potential avenue to treatment of FCI.
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002544:Cerebral Infarction / Q000378:metabolism* / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005260:Female; D005342:Fibrinolysis; D018390:Gene Targeting; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000979:alpha-2-Antiplasmin / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology* / Q000627:therapeutic use