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ShRNA‐mediated gene silencing of t‐PA prevents BBB disruption and elevation of MMP‐12 after ischemic stroke
Author(s) -
Nalamolu Koteswara Rao,
Challa Siva Reddy,
Mohandass Adithya,
Mussman Justin P.,
Ilahi Sadia B.,
Bedadala Mayurnath Reddy,
Klopfenstein Jeffrey D.,
Pinson David M.,
Wang David Z.,
Kalyanasundaram Ramaswamy,
Vemuganti Raghu,
Veeravalli Krishna Kumar
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05550
Subject(s) - extravasation , small hairpin rna , medicine , evans blue , stroke (engine) , ischemia , gene silencing , blood–brain barrier , endogeny , anesthesia , pharmacology , pathology , central nervous system , apoptosis , chemistry , gene knockdown , gene , biochemistry , mechanical engineering , engineering
Post‐stroke induction of endogenous tissue‐type plasminogen activator (t‐PA) is known to promote BBB disruption after ischemic stroke, which contributes to edema, inflammation, hemorrhagic transformations and brain damage. We presently evaluated if this effect of t‐PA leads to the elevation of MMP‐12 in the ischemic brain. Cohorts of adult, male rats were administered with plasmids that express either a t‐PA shRNA or a scrambled control shRNA (1 mg/Kg; i.v.; n=9–13/group) formulated as nanoparticles at 5 min of reperfusion following transient focal middle cerebral artery occlusion. We also have sham‐operated control and untreated ischemia‐induced cohorts. As compared to control shRNA cohort, t‐PA shRNA treated cohort prevented the degradation of tight junction proteins claudin‐5 and ZO‐1, curtailed BBB disruption (studied by Evans blue extravasation into brain), and showed significantly reduced MMP‐12 expression. These results indicate that post‐stroke induced endogenous t‐PA mediated BBB disruption contributes to elevation of MMP‐12 in the ischemic brain. Support or Funding Information This work was supported by the NIH Grant 1R01NS102573‐01A1 to KKV.