Abstract
We hypothesize that endothelial-specific thioredoxin-interacting protein knock-out (EC-TXNIP KO) mice will be more resistant to the neurovascular damage (hemorrhagic-transformation-HT) associated with hyperglycemia (HG) in embolic stroke. Adult-male EC-TXNIP KO and wild-type (WT) littermate mice were injected with-streptozotocin (40 mg/kg, i.p.) for five consecutive days to induce diabetes. Four-weeks after confirming HG, mice were subjected to embolic middle cerebral artery occlusion (eMCAO) followed by tissue plasminogen activator (tPA)-reperfusion (10 mg/kg at 3 h post-eMCAO). After the neurological assessment, animals were sacrificed at 24 h for neurovascular stroke outcomes. There were no differences in cerebrovascular anatomy between the strains. Infarct size, edema, and HT as indicated by hemoglobin (Hb)-the content was significantly higher in HG-WT mice, with or without tPA-reperfusion, compared to normoglycemic WT mice. Hyperglycemic EC-TXNIP KO mice treated with tPA tended to show lower Hb-content, edema, infarct area, and less hemorrhagic score compared to WT hyperglycemic mice. EC-TXNIP KO mice showed decreased expression of inflammatory mediators, apoptosis-associated proteins, and nitrotyrosine levels. Further, vascular endothelial growth factor-A and matrix-metalloproteinases (MMP-9/MMP-3), which degrade junction proteins and increase blood-brain-barrier permeability, were decreased in EC-TXNIP KO mice. Together, these findings suggest that vascular-TXNIP could be a novel therapeutic target for neurovascular damage after stroke.
Highlights
American Diabetes Association reported that diabetic patients have a higher, two to four fold increased risk of ischemic stroke compared to those without diabetes and that increased blood glucose (BG) level is associated with high morbidity and mortality [3]
We determined the mortality rate; all the animals in the NG group survived while three animals died in the HG wild type non-tissue plasminogen activator (tPA) group, two animals in HG wild type with three animals died in the HG wild type non-tPA group, two animals in HG wild type tPA group and one animal died in the EC-Thioredoxin-interacting protein (TXNIP) KO (HG cre/flox-tPA) group. (Figure with tPA group and one animal died in the EC-TXNIP KO (HG cre/flox-tPA) group
We demonstrated that mice with an endothelial cell selective deletion of TXNIP are more resistant to the neurovascular damage associated with STZbased HG with tPA-reperfusion in a murine model of embolic stroke
Summary
Diabetes is a rapidly rising threat that affects 30% of the over 8 million annual stroke patients in the United States [1]. Recent studies identified that hyperglycemia (HG), regardless of diabetes, significantly increases the risk and severity of acute stroke [2]. The. American Diabetes Association reported that diabetic patients have a higher, two to four fold increased risk of ischemic stroke compared to those without diabetes and that increased blood glucose (BG) level is associated with high morbidity and mortality [3]. Worsened post-stroke outcomes and higher mortality were observed in HG patients [6]. This may occur because HG is associated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
