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MicroRNA-30a regulates acute cerebral ischemia-induced blood–brain barrier damage through ZnT4/zinc pathway
Authors:Peng Wang  Rong Pan  John Weaver  Mengjie Jia  Xue Yang  Tianhui Yang  Jia Liang  Ke J Liu
Institution:1.Key Laboratory of Neurodegenerative Diseases of Liaoning Province, Jinzhou Medical University, Jinzhou, China;2.Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
Abstract:The mechanism of early blood–brain barrier (BBB) disruption after stroke has been intensively studied but still not fully understood. Here, we report that microRNA-30a (miR-30a) could mediate BBB damage using both cellular and animal models of ischemic stroke. In the experiments in vitro, inhibition of miR-30a decreased BBB permeability, prevented the degradation of tight junction proteins, and reduced intracellular free zinc in endothelial cells. We found that the zinc transporter ZnT4 was a direct target of negative regulation by miR-30a, and ZnT4/zinc signaling pathway contributed significantly to miR-30a-mediated BBB damage. Consistent with these in vitro findings, treatment with miR-30a inhibitor reduced zinc accumulation, increased the expression of ZnT4, and prevented the loss of tight junction proteins in microvessels of ischemic animals. Furthermore, inhibition of miR-30a, even at 90 min post onset of middle cerebral artery occlusion, prevented BBB damage, reduced infarct volume, and ameliorated neurological deficits. Together, our findings provide novel insights into the mechanisms of cerebral ischemia-induced BBB disruption and indicate miR-30a as a regulator of BBB function that can be an effective therapeutic target for ischemic stroke.
Keywords:Blood–  brain barrier  ischemic stroke  microRNA-30a  zinc  ZnT4
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