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MiR-34a Interacts with Cytochrome c and Shapes Stroke Outcomes
Heng Hu1,2, Emily A Hone3,4, Edward A P Provencher3
1Departments of Physiology and Pharmacology, Center for Basic and Translational Stroke Research; West Virginia University, Morgantown, West Virginia, 26506, USA.
Scientific Reports
|February 26, 2020
Summary
MicroRNA-34a (miR-34a) levels increase during stroke, contributing to blood-brain barrier (BBB) opening and poor outcomes. Inhibiting miR-34a protects the BBB and improves stroke recovery in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Blood-brain barrier (BBB) dysfunction is a hallmark of cerebrovascular diseases like stroke, negatively impacting acute outcomes.
- MicroRNA-34a (miR-34a) has been identified as a regulator of BBB integrity in vitro.
- Understanding miR-34a's role in stroke is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of miR-34a in BBB dysfunction and stroke outcomes.
- To determine if miR-34a directly targets cytochrome c (CYC) in the context of stroke.
- To explore miR-34a as a potential therapeutic target for stroke.
Main Methods:
- Primary cerebrovascular endothelial cells (pCECs) were isolated from mice subjected to transient middle cerebral artery occlusion (tMCAO).
- Real-time PCR was used to quantify miR-34a levels in pCECs.
- BBB permeability, tight junction integrity, and stroke outcomes were assessed in miR-34a knockout mice compared to wild-type controls.
- A dual luciferase reporter gene assay confirmed CYC as a direct target of miR-34a.
Main Results:
- miR-34a levels were elevated in pCECs from tMCAO mice during BBB opening.
- miR-34a knockout significantly reduced BBB permeability and tight junction disruption.
- Stroke outcomes were improved in miR-34a knockout mice compared to wild-type.
- Cytochrome c (CYC) levels were decreased in ischemic tissues of wild-type mice but not in miR-34a knockout mice, confirming CYC as a target.
Conclusions:
- miR-34a plays a critical role in BBB dysfunction and exacerbates stroke outcomes.
- Targeting miR-34a offers a promising therapeutic strategy for stroke.
- This study elucidates a novel mechanism involving miR-34a and CYC in stroke pathophysiology.
