Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats
Bo Yin,*,1 Dan-Dong Li,*,2,3 Shang-Yu Xu,3 Huan Huang,4 Jian Lin,3 Han-Song Sheng,3 Jun-Hao Fang,3 Jin-Ning Song,2 Ming Zhang11Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Departm...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2019-07-01
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| Series: | Neuropsychiatric Disease and Treatment |
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| Online Access: | https://www.dovepress.com/simvastatin-pretreatment-ameliorates-t-pandashinduced-hemorrhage-trans-peer-reviewed-article-NDT |
| _version_ | 1818570798781169664 |
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| author | Yin B Li DD Xu SY Huang H Lin J Sheng HS Fang JH Song JN Zhang M |
| author_facet | Yin B Li DD Xu SY Huang H Lin J Sheng HS Fang JH Song JN Zhang M |
| author_sort | Yin B |
| collection | DOAJ |
| description | Bo Yin,*,1 Dan-Dong Li,*,2,3 Shang-Yu Xu,3 Huan Huang,4 Jian Lin,3 Han-Song Sheng,3 Jun-Hao Fang,3 Jin-Ning Song,2 Ming Zhang11Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital, Medical School of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workBackground: 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.Keywords: simvastatin, acute ischemic stroke, t-PA, MMP-9/TIMP-1, RhoA/ROCK pathway, hemorrhagic transformation |
| first_indexed | 2024-12-14T13:46:38Z |
| format | Article |
| id | doaj.art-e7128b6ea75442bf828d20277904a650 |
| institution | Directory Open Access Journal |
| issn | 1178-2021 |
| language | English |
| last_indexed | 2024-12-14T13:46:38Z |
| publishDate | 2019-07-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Neuropsychiatric Disease and Treatment |
| spelling | doaj.art-e7128b6ea75442bf828d20277904a6502022-12-21T22:59:18ZengDove Medical PressNeuropsychiatric Disease and Treatment1178-20212019-07-01Volume 151993200247149Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic ratsYin BLi DDXu SYHuang HLin JSheng HSFang JHSong JNZhang MBo Yin,*,1 Dan-Dong Li,*,2,3 Shang-Yu Xu,3 Huan Huang,4 Jian Lin,3 Han-Song Sheng,3 Jun-Hao Fang,3 Jin-Ning Song,2 Ming Zhang11Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital, Medical School of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workBackground: 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.Keywords: simvastatin, acute ischemic stroke, t-PA, MMP-9/TIMP-1, RhoA/ROCK pathway, hemorrhagic transformationhttps://www.dovepress.com/simvastatin-pretreatment-ameliorates-t-pandashinduced-hemorrhage-trans-peer-reviewed-article-NDTsimvastatinacute ischemic stroket-PAMMP-9/TIMP-1Rho/ROCK pathwayhemorrhagic transformation |
| spellingShingle | Yin B Li DD Xu SY Huang H Lin J Sheng HS Fang JH Song JN Zhang M Simvastatin pretreatment ameliorates t-PA–induced hemorrhage transformation and MMP-9/TIMP-1 imbalance in thromboembolic cerebral ischemic rats Neuropsychiatric Disease and Treatment simvastatin acute ischemic stroke t-PA MMP-9/TIMP-1 Rho/ROCK pathway hemorrhagic transformation |
| 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 ndash induced hemorrhage transformation and mmp 9 timp 1 imbalance in thromboembolic cerebral ischemic rats |
| topic | simvastatin acute ischemic stroke t-PA MMP-9/TIMP-1 Rho/ROCK pathway hemorrhagic transformation |
| url | https://www.dovepress.com/simvastatin-pretreatment-ameliorates-t-pandashinduced-hemorrhage-trans-peer-reviewed-article-NDT |
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