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Published on: January 23, 2019
Tissue plasminogen activator deficiency preserves neurological function and protects against murine acute ischemic
Hon-Kan Yip1, Chun-Man Yuen2, Kuan-Hung Chen3
1Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Department of Medical Research, China Medical University Hospital,, China Medical University, Taichung 40402, Taiwan.
Background:
We tested the hypothesis that tissue plasminogen activator (tPA) deficiency protected against acute ischemic stroke (AIS)-induced brain injury.
Methods And Results:
Wild-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 1h and then reperfusion followed by hypoxia (11% of oxygen supply for 2h), 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).
Conclusion:
tPA deficiency protected the brain from AIS injury.
