Protective effect of miR-642b-3p against brain injury after intracerebral hemorrhage by targeting SERPINE1.
TL;DR
The findings support that restoration of miR-642b-3p alleviates post-ICH cerebral edema and neurological deficits via targeted inhibition of SERPINE1-mediated inflammation, involving suppression of NLRP3 inflammasome and promotion of M2 polarization.
Abstract
INTRODUCTION The pathological mechanism of post-intracerebral hemorrhage (ICH) brain injury remains incompletely clarified. This study aims to clarify the role and molecular mechanism of miR-642b-3p in ICH, thereby providing a potential candidate target for clinical treatment. MATERIAL AND
Methods
We enrolled 66 ICH patients and 70 matched healthy controls with strict inclusion/exclusion criteria, and used multivariable linear regression to analyze independent correlates of miR-642b-3p and SERPINE1. Collagenase-induced rat ICH models with pre-calculated sample size, random grouping and blinded tests were established, followed by intracerebroventricular injection of 5 nmol/rat miR-642b-3p agomir. Neurological function, brain edema and inflammatory cytokines were detected via mNSS, mLPT and ELISA. LPS-stimulated BV-2 microglia, dual-luciferase assay and SERPINE1 overexpression rescue experiments were adopted to validate the miRNA-target regulatory cascade. NLRP3 inflammasome components and microglial polarization markers were further assessed by qPCR.
Results
miR-642b-3p decreased while SERPINE1 increased in patient serum and rat brain tissue; hematoma volume and GCS score independently predicted their expression. miR-642b-3p overexpression suppressed SERPINE1, relieved edema, improved neurofunction and lowered proinflammatory cytokines in vivo. In LPS-treated BV-2 cells, miR-mimic reversed abnormal SERPINE1 elevation and inflammation, whereas SERPINE1 overexpression abolished such protective effects. Dual-luciferase assay verified direct binding between miR-642b-3p and SERPINE1 3'UTR. Moreover, miR-642b-3p inhibited NLRP3 inflammasome activation and promoted microglial M2 polarization by targeting SERPINE1.
Conclusion
Our findings support that restoration of miR-642b-3p alleviates post-ICH cerebral edema and neurological deficits via targeted inhibition of SERPINE1-mediated inflammation, involving suppression of NLRP3 inflammasome and promotion of M2 polarization. The miR-642b-3p/SERPINE1 axis may serve as a promising therapeutic target for ICH.