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Hypoxia-controlled matrix metalloproteinase-9 hyperexpression promotes behavioral recovery after ischemia
Hongxia Cai1,2, Zhihao Mu1,2, Zhen Jiang1,2
1Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Abstract:
Matrix metalloproteinase-9 (MMP-9) plays a beneficial role in the sub-acute phase after ischemic stroke. However, unrestrained MMP-9 may disrupt the blood-brain barrier (BBB), which has limited its use for the treatment of brain ischemia. In the present study, we constructed lentivirus mediated hypoxia-controlled MMP-9 expression and explored its role after stroke. Hypoxia response element (HRE) was used to confine MMP-9 expression only to the hypoxic region of mouse brain after 120-min transient middle cerebral artery occlusion. Lentiviruses were injected into the peri-infarct area on day 7 after transient ischemia. We found hyperexpression of exogenous HRE-MMP-9 under the control of hypoxia, and its expression was mainly located in neurons and astrocytes without aggravation of BBB damage compared to the CMV group. Furthermore, mice in the HRE-MMP-9 group showed the best behavioral recovery compared with the normal saline, GFP, and SB-3CT groups. Therefore, hypoxia-controlled MMP-9 hyperexpression during the sub-acute phase of ischemia may provide a novel promising approach of gene therapy for stroke.
Insights
This study developed a novel gene therapy for ischemic stroke using hypoxia-controlled matrix metalloproteinase-9 (MMP-9) expression. This approach safely enhanced MMP-9 levels in the affected brain region, leading to improved behavioral recovery in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Gene Therapy
Background:
- Matrix metalloproteinase-9 (MMP-9) has a beneficial role in the sub-acute phase of ischemic stroke.
- Uncontrolled MMP-9 can disrupt the blood-brain barrier (BBB), limiting its therapeutic application.
- Developing targeted MMP-9 delivery strategies is crucial for stroke treatment.
Purpose of the Study:
- To construct a lentivirus-mediated system for hypoxia-controlled MMP-9 expression.
- To investigate the role and safety of this system in a mouse model of ischemic stroke.
- To evaluate the therapeutic potential of hypoxia-controlled MMP-9 gene therapy.
Main Methods:
- Constructed lentivirus with a hypoxia response element (HRE) to control MMP-9 expression.
- Administered lentivirus to the peri-infarct area in mice 7 days after transient middle cerebral artery occlusion (tMCAO).
- Assessed MMP-9 expression, BBB integrity, and behavioral recovery.
Main Results:
- Achieved hypoxia-induced hyperexpression of exogenous MMP-9 specifically in hypoxic brain regions.
- MMP-9 expression was localized to neurons and astrocytes without exacerbating BBB damage.
- Mice treated with HRE-MMP-9 showed superior behavioral recovery compared to control groups.
Conclusions:
- Hypoxia-controlled MMP-9 hyperexpression is a safe and effective strategy in the sub-acute phase of ischemic stroke.
- This targeted gene therapy approach shows promise for improving functional outcomes after stroke.
- Further research into this novel therapeutic strategy for brain ischemia is warranted.
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