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Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats
Background: The use of thrombolysis with tissue-plasminogen activator (t-PA) in patients with acute ischemic stroke (AIS) is limited by increased levels of matrix metalloproteinase-9 (MMP-9) and by the increased risk of hemorrhagic transformation (HT). In this study, we investigated the effects of s...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Dove
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643059/ https://www.ncbi.nlm.nih.gov/pubmed/31410004 http://dx.doi.org/10.2147/NDT.S199371 |
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author | Yin, Bo Li, Dan-Dong Xu, Shang-Yu Huang, Huan Lin, Jian Sheng, Han-Song Fang, Jun-Hao Song, Jin-Ning Zhang, Ming |
author_facet | Yin, Bo Li, Dan-Dong Xu, Shang-Yu Huang, Huan Lin, Jian Sheng, Han-Song Fang, Jun-Hao Song, Jin-Ning Zhang, Ming |
author_sort | Yin, Bo |
collection | PubMed |
description | Background: The use of thrombolysis with tissue-plasminogen activator (t-PA) in patients with acute ischemic stroke (AIS) is limited by increased levels of matrix metalloproteinase-9 (MMP-9) and by the increased risk of hemorrhagic transformation (HT). In this study, we investigated the effects of simvastatin pretreatment on t-PA-induced MMP-9/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and HT aggravation in a rat AIS model. Methods: The rat AIS model was established by autologous blood emboli. Two weeks before surgery, rats were pretreated with simvastatin (60 mg/kg/d), and three hours after surgery, t-PA (10 mg/kg) was administered. MMP-9 and TIMP-1 levels in the infarcted zone and plasma were evaluated by Western blot analysis and ELISA; the level of HT was quantified by determining the hemoglobin content. RhoA activation was determined to clarify the potential effect. Results: The results suggested that pretreatment with simvastatin suppressed the increase in t-PA-induced MMP-9 levels and neutralized the elevated MMP-9/TIMP-1 ratio, but had no effect on TIMP-1 levels. Thrombolysis with t-PA after ischemia improved neurological outcome, but increased intracranial hemorrhage. Moreover, t-PA-induced HT aggravation was reduced by simvastatin pretreatment. In addition, we showed that t-PA-induced activation of RhoA was suppressed by simvastatin, and that t-PA-induced MMP-9/TIMP-1 imbalance and hemorrhage was reduced by Rho kinases (ROCK) inhibitor Y-27632. Conclusion: In this study, we showed that simvastatin pretreatment ameliorated t-PA-induced HT and MMP-9/TIMP-1 imbalance, and demonstrated that the RhoA/ROCK pathway was implicated. |
format | Online Article Text |
id | pubmed-6643059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-66430592019-08-13 Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats Yin, Bo Li, Dan-Dong Xu, Shang-Yu Huang, Huan Lin, Jian Sheng, Han-Song Fang, Jun-Hao Song, Jin-Ning Zhang, Ming Neuropsychiatr Dis Treat Original Research Background: The use of thrombolysis with tissue-plasminogen activator (t-PA) in patients with acute ischemic stroke (AIS) is limited by increased levels of matrix metalloproteinase-9 (MMP-9) and by the increased risk of hemorrhagic transformation (HT). In this study, we investigated the effects of simvastatin pretreatment on t-PA-induced MMP-9/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and HT aggravation in a rat AIS model. Methods: The rat AIS model was established by autologous blood emboli. Two weeks before surgery, rats were pretreated with simvastatin (60 mg/kg/d), and three hours after surgery, t-PA (10 mg/kg) was administered. MMP-9 and TIMP-1 levels in the infarcted zone and plasma were evaluated by Western blot analysis and ELISA; the level of HT was quantified by determining the hemoglobin content. RhoA activation was determined to clarify the potential effect. Results: The results suggested that pretreatment with simvastatin suppressed the increase in t-PA-induced MMP-9 levels and neutralized the elevated MMP-9/TIMP-1 ratio, but had no effect on TIMP-1 levels. Thrombolysis with t-PA after ischemia improved neurological outcome, but increased intracranial hemorrhage. Moreover, t-PA-induced HT aggravation was reduced by simvastatin pretreatment. In addition, we showed that t-PA-induced activation of RhoA was suppressed by simvastatin, and that t-PA-induced MMP-9/TIMP-1 imbalance and hemorrhage was reduced by Rho kinases (ROCK) inhibitor Y-27632. Conclusion: In this study, we showed that simvastatin pretreatment ameliorated t-PA-induced HT and MMP-9/TIMP-1 imbalance, and demonstrated that the RhoA/ROCK pathway was implicated. Dove 2019-07-16 /pmc/articles/PMC6643059/ /pubmed/31410004 http://dx.doi.org/10.2147/NDT.S199371 Text en © 2019 Yin et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Yin, Bo Li, Dan-Dong Xu, Shang-Yu Huang, Huan Lin, Jian Sheng, Han-Song Fang, Jun-Hao Song, Jin-Ning Zhang, Ming Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats |
title | Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats |
title_full | Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats |
title_fullStr | Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats |
title_full_unstemmed | Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats |
title_short | Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats |
title_sort | simvastatin pretreatment ameliorates t-pa–induced hemorrhage transformation and mmp-9/timp-1 imbalance in thromboembolic cerebral ischemic rats |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643059/ https://www.ncbi.nlm.nih.gov/pubmed/31410004 http://dx.doi.org/10.2147/NDT.S199371 |
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