MicroRNA-381 Favors Repair of Nerve Injury Through Regulation of the SDF-1/CXCR4 Signaling Pathway via LRRC4 in Acute Cerebral Ischemia after Cerebral Lymphatic Blockage

Abstract

Background/Aims: Acute cerebral ischemia is a manifestation of cerebral vascular insufficiency and has a high mortality. However, the therapy for acute cerebral ischemia is still limited. This study aimed to investigate the effect of microRNA-381 (miR-381) on the repair of nerve injury in rats with acute cerebral ischemia after cerebral lymphatic blockage (CLB) by targeting leucine-rich repeat C4 protein (LRRC4) through the Stromal cell-derived factor-1/CXC chemokine receptor-4 signaling pathway. Methods: Rat models of CLB and middle cerebral artery occlusion (MCAO) were established, and 56 Wistar rats were divided into sham, MCAO, CLB + MCAO, CLB + MCAO + miR-381 inhibitor, CLB + MCAO + miR-381 mimic, CLB + MCAO + AMD3100 and CLB + MCAO + miR-381 mimic + AMD3100 groups. Modified neurological severity score (mNSS was used to determine nerve injury, TTC staining to measure infarction volume, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and flow cytometry to evaluate cell apoptosis, immunofluorescence to measure BrdU-positive cell number, enzyme-linked immunosorbent assay (ELISA) to determine contents of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), nerve growth factor (NGF) and neurite outgrowth inhibitor -A (Nogo-A), Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting to evaluate expression of miR-381, LRRC4, SDF-1, CXCR4, pERK, Slit2 and vascular endothelial growth factor (VEGF). Results: LRRC4 was a target gene of miR-381. Compared with the results in the CLB + MCAO group, mNSS, infarction volume, apoptosis rate and TNF-α, IL-1β, IL-6 and Nogo-A contents as well as LRRC4 expression in the CLB + MCAO + miR-381 inhibitor and CLB + MCAO + AMD3100 groups were increased (those in the CLB + MCAO + AMD3100 group > those in the CLB + MCAO + miR-381 mimic + AMD3100 group), while BrdU-positive cell number, contents of NGF and IL-10, and expression of SDF-1, CXCR4, pERK, Slit2 and VEGF in brain tissues were decreased (those in the CLB + MCAO + AMD3100 group < those in the CLB + MCAO + miR-381 mimic + AMD3100 group). The results in the CLB + MCAO + mimic group were opposite of those in the CLB + MCAO + miR-381 inhibitor and CLB + MCAO + AMD3100 groups. Conclusion: Taken together, we concluded that up-regulation of miR-381 promoted nerve injury repair in acute cerebral ischemia rats after CLB by negatively regulating LRRC4 through activating the SDF-1/CXCR4 signaling pathway.

RETRACTED ARTICLE: Restored microRNA-326-5p Inhibits Neuronal Apoptosis and Attenuates Mitochondrial Damage via Suppressing STAT3 in Cerebral Ischemia/Reperfusion Injury

“…Rats were allocated into 6 groups (n = 6) and injected with plasmid or miR into lateral cerebroventricular before the establishment of MCAO models, including the sham group, the MCAO group (modeled rats), the NC group (modeled rats with lateral cerebroventricular injection of 5 μL scrambled oligonucleotides [100 μM]), the miR-326-5p agomir group (modeled rats with lateral cerebroventricular injection of 5 μL miR-326-5p agomir [100 μM]), the sh-STAT3 group (modeled rats with lateral cerebroventricular injection of 5 μL STAT3 interference vector [100 μM]) and the miR-326-5p agomir + oe-STAT3 group (modeled rats with lateral cerebroventricular injection of 5 μL miR-326-5p agomir [100 μM] and 5 μL STAT3 overexpression vector [100 μM]) [20,21].…”

miR-548j-5p Regulates Angiogenesis in Peripheral Artery Disease

“…SDF-1 is a chemokine that has a strong chemotactic effect on EPCs. After vascular injury, SDF-1 induces migration of EPCs to the injured area and promotes endothelialization [20,21]. Under hyperglycemic conditions miR-133a was found to be up-regulated and induced endothelial dysfunction through inhibition of eNOS [22].…”

Sitagliptin Stimulates Endothelial Progenitor Cells to Induce Endothelialization in Aneurysm Necks Through the SDF-1/CXCR4/NRF2 Signaling Pathway

“…SDF-1 is a chemokine that has a strong chemotactic effect on hematopoietic stem/endothelial cells. After vascular injury, a high SDF-1 concentration gradient can form locally, thereby inducing endothelial progenitor cells to mobilize from the bone marrow along the concentration gradient to the periphery, further homing to the vascular injury area, and promoting endothelialization repair through adhesion, angiogenesis, and paracrine signals (22,23). Our study showed that sitagliptin promoted not only the migration and angiogenesis of endothelial progenitor cells but also the expression of the provascular cytokines SDF-1 and VEGF by endothelial progenitor cells at the mRNA and protein levels.…”