Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice.

Abstract

BACKGROUND:

Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke.

OBJECTIVES:

To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke.

METHODS:

Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg(-/-)), stromelysin-1 (MMP-3(-/-)), or gelatinase B (MMP-9(-/-)) and their corresponding wild-type (WT) littermates. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice.

RESULTS:

ICB induced by t-PA (10 mg kg(-1)) was significantly less than WT in Plg(-/-) (P < 0.05) and MMP-3(-/-) (P < 0.05) but not in MMP-9(-/-) mice. Furthermore, administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly (P < 0.05) in MMP-3(+/+) mice, but had no effect on MMP-3(-/-) mice. MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was up-regulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment.

CONCLUSIONS:

Our data with gene-deficient mice thus suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.

• Authors: Y Suzuki, N Nagai, K Umemura, D Collen, H R Lijnen
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 5 Issue 8 Pg. 1732-9 (Aug 2007) ISSN: 1538-7933 [Print] England
• PMID: 17596135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Placebos
• Tissue Plasminogen Activator
• Matrix Metalloproteinase 3
• Mmp3 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Gene Expression Regulation
• Intracranial Hemorrhages (enzymology, etiology)
• Ischemia (complications)
• Matrix Metalloproteinase 3 (physiology)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Genetic
• Neurons (metabolism)
• Placebos
• Stroke (blood, complications, drug therapy)
• Thrombolytic Therapy (methods)
• Tissue Plasminogen Activator (therapeutic use)