Tissue plasminogen activator deficiency preserves neurological function and protects against murine acute ischemic stroke

• tPA deficiency impeded intracerebral bleeding through reducing MMP-9 activity after acute IS.
• Inhibiting tPA-gene expression protected brain function from acute IS injury.
• tPA deficiency predicted prognostic outcomes after acute IS.

BackgroundWe tested the hypothesis that tissue plasminogen activator (tPA) deficiency protected against acute ischemic stroke (AIS)-induced brain injury.Methods and ResultsWild-type mice (n = 54) were categorized into group 1 (sham control, n = 18) and group 3 [AIS by permanent ligation of left common carotid artery (CCA) and cramping right CCA for 1 h and then reperfusion followed by hypoxia (11% of oxygen supply for 2 h), n = 36]. Similarly, tPA knockout (tPA−/−) mice (n = 54) were randomized into group 2 (sham control, n = 18) and group 4 (AIS, n = 36). By day 28 after AIS procedure, mortality rate was higher in group 3 (77.8%) than in group 4 (38.9%) and lowest in groups 1 (0%) and 2 (0%) (p < 0.001). By days 3 and 28, MRI demonstrated a pattern of changes in brain-infarct volume identical to that of mortality among four groups (p < 0.001). By day 28, protein expressions of inflammatory (MMP-9, TNF-α, NF-κB, iNOS, PAI-1, RANTES), oxidative (NOX-1, NOX-2, oxidized protein), apoptotic (cleaved caspase-3 & PARP, Bax), and fibrotic (Smad3, TGF-β) biomarkers and cellular expressions of inflammation (CD11, F4/80, GFAP), DNA-damage (γ-H2AX) and brain-edema (AQP4) markers exhibited an identical pattern compared to that of mortality (all p < 0.001), whereas protein expressions of endothelial (eNOS, CD31), anti-fibrotic (Smad1/5, BMP-2) biomarkers, and number of small vessels displayed an opposite pattern (all p < 0.001) among four groups. Expressions of protein and cellular angiogenesis markers (VEGF, SDF-1α, CXCR4) were progressively increased from groups 1 and 2 to group 4 (all p < 0.0001).ConclusiontPA deficiency protected the brain from AIS injury.