MiR‐21‐5p/dual‐specificity phosphatase 8 signalling mediates the anti‐inflammatory effect of haem oxygenase‐1 in aged intracerebral haemorrhage rats

Abstract

Intracerebral haemorrhage (ICH) is a severe neurological disorder caused by bleeding within the brain tissue. Inflammation has been implicated in ICH pathogenesis and is a potential therapeutic target for ICH. Haemin, an activator of haem oxygenase-1 (HO-1), rapidly increases HO-1 protein expression and activity and has been shown to distinctly affect anti-inflammatory functions after central nervous system (CNS) injury. However, less is known about the mechanisms that underlie the antiinflammatory effects of haemin in aged rats post-ICH. Here, we performed microarray analysis to identify miRNAs that respond strongly to HO-1 regulation in ICH rats and found that miR-21-5p induced the most significant change. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Gene Ontology (GO) analysis, we focused on dual-specificity phosphatase 8 (DUSP8) from the predicted miR-21-5p targets. Luciferase reporter assays confirmed that miR-21-5p bound directly to DUSP8. MiR-21-5p upregulation in vitro downregulated DUSP8 expression. Importantly, intracerebroventricularly injecting antagomir for miR-21-5p (A-miR-21-5p), which was used to inhibit miR-21-5p in aged ICH rats, significantly reduced the neurological defects, repaired cognitive impairment, alleviated blood-brain barrier (BBB) permeability, inhibited neuronal apoptosis posthaemorrhage and accelerated haematoma absorption. In addition, serum miR-21-5p levels were notably elevated in patients relative to healthy individuals and were correlated with National Institutes of Health Stroke Scale (NIHSS) scores and clinical outcomes. In summary, A-miR-21-5p increased HO-1 expression in cerebral haematomas, thus eliciting the

Diagnostic Role of Plasma MicroRNA-21 in Stable and Unstable Angina Patients and Association with Aging

“…Moreover, very recently, it was reported that expression of serum miR-21 levels was notably elevated in atherosclerotic subjects and stroke patients relative to healthy individuals. Likewise, they also found that miR-21 strongly regulated the anti-inflammatory effect of haem oxygenase-1 (HO-1) in aged intracerebral hemorrhagic rats [24]. Besides, plasma microRNA-21 was also significantly correlated with platelet extracellular vesicles (EVs) in stable coronary artery disease patients [25].…”

<p>Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization</p>

“…Rapidly accumulating evidences have indicated that miRNAs are crucial regulators in ICH. 13,14 Exosomal miRNAs expression varies widely in different cell types and pathological states, and miRmodified Exos may alter its function. MiR-146a-5p is highly conserved among humans, mice, and rats.…”

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

“…Intracerebral hemorrhage (ICH) occurs when a weakened vessel ruptures and bleeds into the surrounding brain [29,30]. Various forms of cell death have been identified after ICH, including apoptosis, necrosis, and autophagy in humans and experimental animals, and autophagic cell death in animal models [31][32][33]. Although inhibiting apoptosis, necrosis, and autophagy can improve outcomes in animals subjected to experimental ICH, no successful clinical trials using cell-death inhibitor monotherapy have been reported [34][35][36].…”