Abstract
Previous studies have reported that miR-27a-3p is down-regulated in the serum of patients with intracerebral hemorrhage (ICH), but the implication of miR-27a-3p down-regulation in post-ICH complications remains elusive. Here we verified miR-27a-3p levels in the serum of ICH patients by real-time PCR and observed that miR-27a-3p is also significantly reduced in the serum of these patients. We then further investigated the effect of miR-27a-3p on post-ICH complications by intraventricular administration of a miR-27a-3p mimic in rats with collagenase-induced ICH. We found that the hemorrhage markedly reduced miR-27a-3p levels in the hematoma, perihematomal tissue, and serum and that intracerebroventricular administration of the miR-27a-3p mimic alleviated behavioral deficits 24 h after ICH. Moreover, ICH-induced brain edema, vascular leakage, and leukocyte infiltration were also attenuated by this mimic. Of note, miR-27a-3p mimic treatment also inhibited neuronal apoptosis and microglia activation in the perihematomal zone. We further observed that the miR-27a-3p mimic suppressed the up-regulation of aquaporin-11 (AQP11) in the perihematomal area and in rat brain microvascular endothelial cells (BMECs). Moreover, miR-27a-3p down-regulation increased BMEC monolayer permeability and impaired BMEC proliferation and migration. In conclusion, miR-27a-3p down-regulation contributes to brain edema, blood-brain barrier disruption, neuron loss, and neurological deficits following ICH. We conclude that application of exogenous miR-27a-3p may protect against post-ICH complications by targeting AQP11 in the capillary endothelial cells of the brain.
Highlights
Previous studies have reported that miR-27a-3p is down-regulated in the serum of patients with intracerebral hemorrhage (ICH), but the implication of miR-27a-3p down-regulation in post-ICH complications remains elusive
We found that the hemorrhage markedly reduced miR-27a-3p levels in the hematoma, perihematomal tissue, and serum and that intracerebroventricular administration of the miR-27a-3p mimic alleviated behavioral deficits 24 h after ICH
We further observed that the miR-27a-3p mimic suppressed the up-regulation of aquaporin-11 (AQP11) in the perihematomal area and in rat brain microvascular endothelial cells (BMECs)
Summary
To verify previous miRNA array data [14], serum levels of miR-27a-3p in ICH patients and healthy subjects were measured by real-time PCR. The number of positively stained neurons was significantly increased in the perihematomal area of ICH rats (189 Ϯ 39), whereas the miR-27a-3p mimic reduced the number of dying neurons adjacent to the hematoma (62 Ϯ 14) (Fig. 5, B and E). The number of OX-42-positive microglia in the perihematomal area was remarkably elevated in the ICH group (226 Ϯ 56), and it was significantly reduced by miR-27a-3p mimic treatment (121 Ϯ 46) (Fig. 5, C and F). The expression of AQP11 was found to be significantly increased at both the mRNA and protein levels in the perihematomal region of ICH rats compared with sham-operated brain parenchyma (Fig. 6, A and B). In BMECs, the expression levels of AQP11 mRNA and protein were significantly decreased by the miR-27a-3p mimic and increased by an miR-27a-3p inhibitor (Fig. 6, C and D), which was consistent with in vivo findings. Inhibition of miR-27a-3p increased the permeability of the BMEC monolayer and reduced the proliferative and migratory abilities of BMECs
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