Role of Plasminogen System Components in Focal Cerebral Ischemic Infarction

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 α 2 -antiplasmin (PAI-1 −/− or α 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. α 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 α 2 -AP −/− ) after intravenous injection of human α 2 -AP. Injection into α 2 -AP −/− mice of Fab fragments of affinospecific rabbit IgG against human α 2 -AP, after injection of 200 μg human α 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-1 gene inactivation) increases infarct size, and (2) reduction of Plg activity ( Plg gene inactivation or α 2 -AP injection) increases whereas its augmentation (α 2 - AP gene inactivation or α 2 -AP neutralization) reduces infarct size. Inhibition of α 2 -AP may constitute a potential avenue to treatment of FCI.