Role of plasminogen system components in focal cerebral ischemic infarction - A gene targeting and gene transfer study in mice

Article

关键词: ADENOVIRUS-MEDIATED TRANSFER;    ACTIVATOR INHIBITOR-1;    DEFICIENT MICE;    INTRAVENOUS THROMBOLYSIS;    NEURONAL DEGENERATION;    GENERATION;    HIPPOCAMPUS;    DISORDERS;    TYPE-5;    STROKE;   

DOI  :  10.1161/01.CIR.99.18.2440

来源: SCIE

【 摘 要 】

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 alpha(2)-antiplasmin (PAI-1(-/-) or alpha(2)-AP(-/-)). Methods and 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 mm(3) (mean+/-SEM), uPA(-/-) mice had similar infarcts (7.8+/-1.0 mm(3), P=NS), tPA(-/-) mice smaller (2.6+/-0.80 mm(3), P<0.0001), PAI-1(-/-) mice larger (16+/-0.52 mm(3), P<0.0001), and Plg(-/-) mice larger (12+/-1.2 mm(3), P=0.037) infarcts. alpha(2)-AP(-/-) mice had smaller infarcts (2.2+/-1.1 mm(3), P<0.0001 versus wild-type), which increased to 13 +/-2.5 mm(3) (P<0.005 versus alpha(2)-AP(-/-)) after intravenous injection of human alpha(2)-AP. Injection into,alpha(2)-Ap(-/-) mice of Fab fragments of affinospecific rabbit IgG against human alpha(2)-AP, after injection of 200 mu g human alpha(2)-AP, reduced FCI from 11+/-1.5 to 5.1+/-1.1 mm(3) (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-I gene inactivation) increases infarct size, and (2) reduction of Pig activity (Plg gene inactivation or alpha(2)-AP injection) increases whereas its augmentation (alpha(2)-AP gene inactivation or alpha(2)-AP neutralization) reduces infarct size. Inhibition of alpha(2)-AP may constitute a potential avenue to treatment of FCI.

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