Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy
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 wer...
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MDPI AG
2021-09-01
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| author | Mohd. Salman Saifudeen Ismael Lexiao Li Heba A. Ahmed Michelle A. Puchowicz Tauheed Ishrat |
| author_facet | Mohd. Salman Saifudeen Ismael Lexiao Li Heba A. Ahmed Michelle A. Puchowicz Tauheed Ishrat |
| author_sort | Mohd. Salman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T06:17:38Z |
| format | Article |
| id | doaj.art-d411629d00e242999235d876bece756d |
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| language | English |
| last_indexed | 2024-03-10T06:17:38Z |
| publishDate | 2021-09-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-d411629d00e242999235d876bece756d2023-11-22T19:35:32ZengMDPI AGPharmaceuticals1424-82472021-09-01141098310.3390/ph14100983Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic TherapyMohd. Salman0Saifudeen Ismael1Lexiao Li2Heba A. Ahmed3Michelle A. Puchowicz4Tauheed Ishrat5Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Pediatrics, The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USAWe 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.https://www.mdpi.com/1424-8247/14/10/983hyperglycemiaendothelial-specific TXNIP deletiontissue plasminogen activatorhemorrhagic transformationembolic stroke |
| spellingShingle | Mohd. Salman Saifudeen Ismael Lexiao Li Heba A. Ahmed Michelle A. Puchowicz Tauheed Ishrat Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy Pharmaceuticals hyperglycemia endothelial-specific TXNIP deletion tissue plasminogen activator hemorrhagic transformation embolic stroke |
| title | Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy |
| title_full | Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy |
| title_fullStr | Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy |
| title_full_unstemmed | Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy |
| title_short | Endothelial Thioredoxin-Interacting Protein Depletion Reduces Hemorrhagic Transformation in Hyperglycemic Mice after Embolic Stroke and Thrombolytic Therapy |
| title_sort | endothelial thioredoxin interacting protein depletion reduces hemorrhagic transformation in hyperglycemic mice after embolic stroke and thrombolytic therapy |
| topic | hyperglycemia endothelial-specific TXNIP deletion tissue plasminogen activator hemorrhagic transformation embolic stroke |
| url | https://www.mdpi.com/1424-8247/14/10/983 |
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