Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage.
Serine proteases, such as thrombin and tissue-type plasminogen activator, play an important role in brain injury after intracerebral hemorrhage and other neurologic disorders. Plasminogen activator inhibitor-1 is one of the serine protease inhibitors, or serpins. The balance between serine proteases and serpins may affect the outcome of intracerebral hemorrhage. The purpose of this study was to determine whether plasminogen activator inhibitor-1 and tissue-type plasminogen activator are upregulated after intracerebral hemorrhage and the role that thrombin plays in that induction. Plasminogen activator inhibitor-1 protein levels were upregulated after intracerebral hemorrhage. Brain plasminogen activator inhibitor-1 content also increased after thrombin infusion in a dose-dependent manner. Hirudin, a specific thrombin inhibitor, blocked the upregulation of plasminogen activator inhibitor-1 after intracerebral hemorrhage. Time courses showed that plasminogen activator inhibitor-1 levels around the hematoma peaked at the first day. Plasminogen activator inhibitor-1-positive cells were detected in the perihematomal area and the ipsilateral basal ganglia after thrombin infusion, but not in the contralateral hemisphere. Plasminogen activator inhibitor-1 messenger RNA levels were increased at 24 hours after intracerebral hemorrhage and after thrombin infusion. However, tissue-type plasminogen activator protein levels were the same in the control, whole-blood, and thrombin-infusion groups. In conclusion, intracerebral hemorrhage and thrombin infusion stimulate plasminogen activator inhibitor-1 but not tissue-type plasminogen activator production in the brain. The upregulation of plasminogen activator inhibitor-1 may be neuroprotective by limiting thrombin or other serine protease-induced toxicity.
Hua
Ya
Y
Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109-0532, USA.
Xi
Guohua
G
Keep
Richard F
RF
Wu
Jimin
J
Jiang
Yajun
Y
Hoff
Julian T
JT
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D004790:Enzyme Induction / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D015854:Up-Regulation
D005343:Fibrinolytic Agents; D006629:Hirudins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D013917:Thrombin; D010959:Tissue Plasminogen Activator