Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism
Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP acti...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2014-01-01
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| Series: | Stroke Research and Treatment |
| Online Access: | http://dx.doi.org/10.1155/2014/560491 |
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| author | Tauheed Ishrat Anna Kozak Ahmed Alhusban Bindu Pillai Maribeth H. Johnson Azza B. El-Remessy Adviye Ergul Susan C. Fagan |
| author_facet | Tauheed Ishrat Anna Kozak Ahmed Alhusban Bindu Pillai Maribeth H. Johnson Azza B. El-Remessy Adviye Ergul Susan C. Fagan |
| author_sort | Tauheed Ishrat |
| collection | DOAJ |
| description | Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n = 9–14/group; a total of 99) were treated in a factorial design with candesartan 1 mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30 mg/kg IP or GM6001 50 mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3 h of middle cerebral artery occlusion (MCAO) and 21 h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone (P=0.0011) and in combination with FeTPPs (P=0.0016). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT (P<0.0001) and worsened neurologic score (P=0.028). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism. |
| format | Article |
| id | doaj-art-86a8acfdb8f24dad8a868813947047a2 |
| institution | OA Journals |
| issn | 2090-8105 2042-0056 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stroke Research and Treatment |
| spelling | doaj-art-86a8acfdb8f24dad8a868813947047a22025-08-20T02:08:47ZengWileyStroke Research and Treatment2090-81052042-00562014-01-01201410.1155/2014/560491560491Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin AntagonismTauheed Ishrat0Anna Kozak1Ahmed Alhusban2Bindu Pillai3Maribeth H. Johnson4Azza B. El-Remessy5Adviye Ergul6Susan C. Fagan7Charlie Norwood VA Medical Center, Augusta, GA 30912, USACharlie Norwood VA Medical Center, Augusta, GA 30912, USACharlie Norwood VA Medical Center, Augusta, GA 30912, USACharlie Norwood VA Medical Center, Augusta, GA 30912, USADepartment of Biostatistics, Georgia Regents University, Augusta, GA 30912, USACharlie Norwood VA Medical Center, Augusta, GA 30912, USACharlie Norwood VA Medical Center, Augusta, GA 30912, USACharlie Norwood VA Medical Center, Augusta, GA 30912, USABackground and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n = 9–14/group; a total of 99) were treated in a factorial design with candesartan 1 mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30 mg/kg IP or GM6001 50 mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3 h of middle cerebral artery occlusion (MCAO) and 21 h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone (P=0.0011) and in combination with FeTPPs (P=0.0016). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT (P<0.0001) and worsened neurologic score (P=0.028). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism.http://dx.doi.org/10.1155/2014/560491 |
| spellingShingle | Tauheed Ishrat Anna Kozak Ahmed Alhusban Bindu Pillai Maribeth H. Johnson Azza B. El-Remessy Adviye Ergul Susan C. Fagan Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism Stroke Research and Treatment |
| title | Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism |
| title_full | Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism |
| title_fullStr | Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism |
| title_full_unstemmed | Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism |
| title_short | Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism |
| title_sort | role of matrix metalloproteinase activity in the neurovascular protective effects of angiotensin antagonism |
| url | http://dx.doi.org/10.1155/2014/560491 |
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